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BIOPHARMACEUTICS &
PHARMACOKINETICS
4th PROFESSIONAL
GHULAM MURTAZA HAMAD
4th PROFF. EVENING
PUNJAB UNIVERSITY COLLEGE OF PHARMACY, LAHORE
Reference
Dr. Nadeem Irfan Bukhari Lectures
Shargel – Applied Biopharmaceutics and
Pharmacokinetics, 7th edition
MADAN PL – Biopharmaceutics and
Pharmacokinetics, 2nd edition
Gilbert S Banker – Modern Pharmaceutics, 4th
edition
GM Hamad
TABLE OF CONTENTS
Contents
1. Definitions and Terminology
2. Gastrointestinal Absorption
3. Biological Half Life and Volume of Distribution
4. Drug Clearance
5. Linear and Non-linear Pharmacokinetics
6. Bioavailability and Bioequivalence
7. Concept of Compartment Models
8. Multiple Dosage Regimen
9. Elimination of Drugs
10. Protein Binding
11. Pharmacokinetic Variations in Disease State
12. Intravenous Infusion
13. Biopharmaceutical Aspects in Developing a Dosage Form
14. In-Vitro-In-Vivo Correlation (IVIVC)
GM Hamad
DEFINITIONS AND TERMINOLOGY
BIOPHARMACEUTICS
• “Biopharmaceutics interrelates physicochemical properties of drug,
characteristics of dosage form, and site (route) of administration to the
rate and extent of systemic drug absorption”
• Biopharmaceutics encompasses factors that influence:
1. Stability of drug within drug product
2. Release of drug from drug product
3. Rate of dissolution/release of drug at the absorption site
4. Systemic absorption of drug.
SCHEME DEMONSTRATING THE DYNAMIC RELATIONSHIP BETWEEN THE DRUG,
THE DRUG PRODUCT, AND THE PHARMACOLOGIC EFFECT
• Efficacy (in-vivo performance) and safety of drug product critically
depends on:
- Physicochemical characteristics of active pharmaceutical
ingredient (API/drug substance)
- Characteristics of dosage form.
- Features of the route of administration.
• Sequence of events to elicit a therapeutic effect: (LADMER)
- Administration (either by an oral, intravenous, subcutaneous,
transdermal, etc. route)
- Liberation (release) of drug from dosage form in a predictable and
characterizable manner.
- Absorption (into the blood)
- Distribution (+ to the site of action)
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- Metabolism
- Excretion
- Response (Therapeutic effect)
• Studies in biopharmaceutics use both in vitro and in vivo methods.
- In vitro methods are procedures employing test apparatus and
equipment without involving laboratory animals or humans.
- In vivo methods are more complex studies involving human
subjects or laboratory animals.
PHARMACOKINETICS
• Pharmacokinetics is the science of the kinetics of drug absorption,
distribution, and elimination (i.e. metabolism and excretion)
• The description of drug distribution and elimination is termed drug
disposition.
• The study of pharmacokinetics involves both experimental and
theoretical approaches.
• The experimental aspect of pharmacokinetics involves the development
of biologic sampling techniques, analytical methods for the
measurement of drugs and metabolites, and procedures that facilitate
data collection and manipulation.
• The theoretical aspect of pharmacokinetics involves the development of
pharmacokinetic models that predict drug disposition after drug
administration.
• The application of statistics is an integral part of pharmacokinetic
studies. Statistical methods are used for pharmacokinetic parameter
estimation and data interpretation ultimately for the purpose of
designing and predicting optimal dosing regimens for individuals or
groups of patients. Statistical methods are applied to pharmacokinetic
models to determine data error and structural model deviations.
CLASSICAL PHARMACOKINETICS
• A study of theoretical models focusing mostly on model development
and parameterization.
POPULATION PHARMACOKINETICS
• A study of pharmacokinetic differences of drugs in various population
groups.
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GM Hamad
CLINICAL PHARMACOKINETICS
• A multidisciplinary approach to individually optimized dosing strategies
for a specific patient based on the patient's disease state and patient-
specific considerations.
• Clinical Pharmacokinetics involves in optimum dosing regimens to
produce desired pharmacologic response in majority of anticipated
patient population.
- Largely dependent on intra- and inter-individual variations which
results in in either a subtherapeutic or toxic response thus, may
requiring adjustment of the dosing regimen.
• Clinical pharmacokinetics is the application of pharmacokinetic methods
to drug therapy.
PHARMACODYNAMICS
• Pharmacodynamics is the study of the biochemical and physiological
effects of drugs on the body; this includes the mechanisms of drug
action and the relationship between drug concentration and effect.
RELATIONSHIP OF BIOPHARMACEUTICS WITH PHARMACOKINETICS
AND PHARMACODYNAMICS
• Drug action depends upon biopharmaceutics and pharmacokinetics. It
interrelates the blood drug concentration to:
- Sub-therapeutic (drug concentration below the MEC)
- Toxic response (drug concentration above the MEC)
- Onset of drug action
- Duration of drug action
DRUG ALTERNATIVES
• Alternatives - (of one or more things) available as another possibility or
choice.
1. PHARMACEUTICAL ALTERNATIVES
• Pharmaceutical alternatives - Drug products that contain same APIs but
as different salts/ esters/ complex or forms.
- Tetracycline phosphate or tetracycline HCl equivalent to 250 mg
tetracycline base.
- Different dosage forms and strengths within a product line by a
single manufacturer.
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GM Hamad
- Examples
i. Extended-release and immediate release dosage forms of
same APIs.
ii. Tablet and Capsule containing the same API in the same
dosage strength.
2. THERAPEUTIC ALTERNATIVES
• Therapeutic alternatives - products containing different API that are
indicated for the same therapeutic or clinical objectives.
- From same pharmacologic class and are expected to have the
same therapeutic effect.
- E.g., ibuprofen and aspirin
DRUG EQUIVALENTS
• Equivalents - equal in value, amount, function, meaning, etc.
1. PHARMACEUTICAL EQUIVALENTS
• Pharmaceutical (Chemical) equivalents are the products:
- Having same APIs (same salt or ester)
- Having same strength, quality and purity
- Used through the same route
- They are also therapeutic equivalents
- They may differ in characteristics such as shape, color, flavor,
scoring configuration, release mechanisms, packaging, excipients,
expiration time, and, within certain limits, labeling.
2. THERAPEUTICAL EQUIVALENTS
• Therapeutic equivalents – Products which are:
- Pharmaceutical equivalents (same APIs, amount of APIs, dosage
forms, routes)
- Generic equivalent (having same APIs as the same salt in same
dosage form (but made by a different manufacturer).
- Same bioavailability (Bioequivalent)
- Expected to have same clinical effect and safety profile when
administered under the conditions specified in the labeling.
DRUG SUBSTITUTION
• Substitution – act of providing a thing in place of another (always giving
an alternative)
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GM Hamad
1. PHARMACEUTICAL SUBSTITUTION
• Pharmaceutical substitution - Dispensing a pharmaceutical alternative
for a prescribed drug product.
- E.g. Dispensing of ampicillin suspension in place of ampicillin
capsules.
- E.g. Tetracycline HCl in place of tetracycline phosphate.
- Generally, requires the physician's approval.
2. THERAPEUTIC SUBSTITUTION
• Therapeutic substitution - Dispensing a therapeutic alternative in place
of the prescribed drug product.
- For example, ibuprofen instead of naproxen.
3. GENERIC SUBSTITUTION
• Generic substitution - dispensing a different brand or an unbranded drug
product in place of the prescribed drug product.
- Substituted drug product must be Pharmaceutical equivalents
(having same API as same salt in same dosage form but is made by
a different manufacturer.
- E.g. Substitution of Motrin brand of ibuprofen in place of Advil
brand of ibuprofen if permitted by physician.
GENERIC EQUIVALENCE
• These are the same API’s in same salts, same chemical form and dosage
forms, ideally bioequivalent pharmaceutical content.
BIOEQUIVALENCE
• Relationship in terms of bioavailability, therapeutic response, or a set of
established standards of one drug product to another.
BIOEQUIVALENT DRUG PRODUCTS
• This term describes pharmaceutical equivalent or pharmaceutical
alternative products that display comparable bioavailability when
studied under similar experimental conditions.
BIOAVAILABILITY
• Bioavailability means the rate and extent to which the active ingredient
or active moiety is absorbed from a drug product and becomes available
at the site of action. For drug products that are not intended to be
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GM Hamad
absorbed into the bloodstream, bioavailability may be assessed by
measurements intended to reflect the rate and extent to which the
active ingredient or active moiety becomes available at the site of
action.
ABSOLUTE BIOAVAILABILITY
• The absolute bioavailability of drug is the systemic availability of a drug
after extravascular administration compared to IV dosing.
• The absolute bioavailability of a drug is generally measured by
comparing the respective AUCs after extravascular and IV
administration.
• Absolute bioavailability after oral drug administration using plasma data
can be determined as follows:
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐴𝑈𝐶] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂
[𝐴𝑈𝐶]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉
• Absolute availability using urinary drug excretion data can be
determined by the following:
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐷 𝑢
∞] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂
[𝐷 𝑢
∞]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉
RELATIVE BIOAVAILABILITY
• Relative (apparent) bioavailability is the bioavailability of the drug from a
drug product as compared to a recognized standard.
• The availability of drug in the formulation is compared to the availability
of drug in a standard dosage formulation, usually a solution of the pure
drug evaluated in a crossover study.
• The relative bioavailability of two drug products given at the same
dosage level and by the same route of administration can be obtained
using the following equation:
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐴𝑈𝐶] 𝐴
[𝐴𝑈𝐶] 𝐵
- where drug product B is the recognized reference standard. This
fraction may be multiplied by 100 to give percent relative
bioavailability.
• When different doses are administered, a correction for the size of the
dose is made, as in the following equation:
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GM Hamad
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐴𝑈𝐶] 𝐴 / 𝐷𝑜𝑠𝑒 𝐴
[𝐴𝑈𝐶] 𝐵 / 𝐷𝑜𝑠𝑒 𝐵
• Urinary drug excretion data may also be used to measure relative
availability, as long as the total amount of intact drug excreted in the
urine is collected. The percent relative availability using urinary
excretion data can be determined as follows:
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐷 𝑢
∞] 𝐴
[𝐷 𝑢
∞] 𝐵
- where [Du]∞
is the total amount of drug excreted in the urine.
DRUG ELIMINATION
• Drug elimination refers to the irreversible removal of drug from the body
by all routes of elimination.
• Drug elimination is usually divided into two major components:
- Excretion
- Biotransformation
EXCRETION
• Drug excretion is the removal of the intact drug.
• Nonvolatile and polar drugs are excreted mainly by renal excretion, a
process in which the drug passes through the kidney to the bladder and
ultimately into the urine.
• Other pathways for drug excretion may include the excretion of drug
into bile, sweat, saliva, milk (via lactation), or other body fluids.
• Volatile drugs, such as gaseous anesthetics, alcohol, or drugs with high
volatility, are excreted via the lungs into expired air.
BIOTRANSFORMATION
• Biotransformation or drug metabolism is the process by which the drug
is chemically converted in the body to a metabolite.
• Biotransformation is usually an enzymatic process. A few drugs may also
be changed chemically by a nonenzymatic process (e.g. ester hydrolysis).
The enzymes involved in the biotransformation of drugs are located
mainly in the liver.
• Other tissues such as kidney, lung, small intestine, and skin also contain
biotransformation enzymes.
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DRUG CLEARANCE
• Drug clearance is defined as the fixed volume of fluid (containing the
drug) removed from the drug per unit of time. The units for clearance
are volume/time (e.g. mL/min, L/h).
• Drug clearance is a pharmacokinetic term for describing drug elimination
from the body without identifying the mechanism of the process.
• Drug clearance (also called body clearance or total body clearance)
considers the entire body as a single drug-eliminating system from which
many unidentified elimination processes may occur.
DRUG DISPOSITION
• It refers to the fate of drug after absorption. On reaching bloodstream,
drugs are simultaneously distributed throughout body and eliminated.
• Distribution usually occurs much more rapidly than elimination. Rate of
distribution to tissues of each organ is determined by blood flow
perfusing organs and ease with which drug molecules cross capillary wall
and penetrate cells of particular tissue.
OTHER TERMINOLOGY
REFERENCE LISTED DRUG (RLD)
• Reference listed drug (RLD) - the drug product on which an applicant
relies when seeking approval of an Abbreviated New Drug Application
(ANDA).
- RLD is generally the brand-name drug that has a full New Drug
Application (NDA).
- The FDA designates a single reference listed drug as the standard
to which all generic versions must be shown to be bioequivalent.
MULTISOURCE DRUG PRODUCT
• Multisource drug product is a drug product that contains the same
active drug substance in the same dosage form and is marketed by more
than one pharmaceutical manufacturer.
SINGLE SOURCE DRUG PRODUCT
• Single source drug product is a drug product for which patent has not
yet expired or has certain exclusivities so that only one manufacturer
can make it.
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GASTROINTESTINAL ABSORPTION
INTRODUCTION
• It is defined as “the process of movement of unchanged drug from the
site of administration to the systemic circulation.
• There always present a correlation between plasma concentration of a
drug and the therapeutic response thus, absorption can also be defined
as the “process of movement of unchanged drug from the site of
administration to the site of measurement. i.e. plasma”.
STRUCTURE OF CELL MEMBRANE
• Cell membrane separates living cell from nonliving surroundings.
- Thin barrier = 8 nm thick
• Controls traffic in and out of the cell
- Selectively permeable: allows some substances to cross more
easily. than others.
- Hydrophobic vs hydrophilic
• Made of phospholipids, proteins and other macromolecules.
• Proteins determine membrane’s specific functions.
- Cell membrane and organelle membranes each have unique
collections of proteins.
• Membrane proteins:
- Peripheral proteins
▪ Loosely bound to surface of membrane.
▪ Cell surface identity marker (antigens)
• Integral proteins:
- Penetrate lipid bilayer, usually across whole membrane
- Transmembrane protein transport proteins
▪ Channels, permeases (pumps)
PHYSIOLOGICAL FACTORS AFFECTING ORAL ABSORPTION
• Passage of drugs across membrane.
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GM Hamad
1. Passive diffusion
2. Pore transport
3. Active transport
4. Facilitated diffusion
5. Pinocytosis
6. Ion pair formation
MECHANISMS OF DRUG ABSORPTION
1. PASSIVE DIFFUSION
CHARACTERISTICS
• Diffusion
- Movement from high to low concentration.
• Major process for absorption of more than 90% of drugs.
• Non-ionic diffusion.
• Driving force: Concentration or electrochemical gradient.
• Difference in the drug concentration on either side of the membrane.
• Drug movement is a result of kinetic energy of molecules.
FICK’S FIRST LAW OF DIFFUSION
• Expressed by Fick’s first law of diffusion:
- “The drug molecules diffuse from a region of higher concentration
to one of lower concentration until equilibrium is attained and the
rate of diffusion is directly proportional to the concentration
gradient across the membrane”.
dQ
dt
=
D A Km/w
h
(CGIT − CP)
- Where,
▪ dQ/dt = rate of drug diffusion (amount/time)
▪ D = diffusion coefficient of the drug
▪ A= surface area of the absorbing membrane for drug
diffusion
▪ Km/w = partition coefficient of drug between the lipoidal
membrane and the aqueous GI fluids
▪ h = thickness of the membrane
▪ (CGIT – Cp) = difference in the concentration of drug in the
GI fluids and the plasma (Concentration Gradient)
- SINK CONDITION
▪ The passively absorbed drug enters blood, rapidly swept
away and distributed into a larger volume of body fluids.
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▪ Hence, the concentration of drug at absorption site CGIT
is maintained greater than the concentration in the
plasma. Such a condition is called as sink condition for
drug absorption.
▪ Under usual absorption conditions, D, A, Km/w and h are
constants, the term D A Km/w /h can be replaced by a
combined constant P called as permeability coefficient.
▪ Permeability: Ease with which a drug can permeate or
diffuse through a membrane.
▪ Due to sink conditions, the C is very small in comparison
to CGIT.
dQ
dt
= P CGIT
2. PORE TRANSPORT
• Also known as convective transport, bulk flow or filtration.
• Important in the absorption of low mol. Wt. (less than 100). Low
molecular size (smaller than the diameter of the pore) and generally
water-soluble drugs e.g. urea, water and sugars.
• The driving force for the passage of the drugs is the hydrostatic or the
osmotic pressure difference across the membrane.
• Mechanism – through the protein channel present in the cell membrane.
• Drug permeation through pore transport – renal excretion, removal of
drug from CSF and entry of drug into the liver.
• Rate of absorption via pore transport depends on the number and size
of the pores, and given as follows:
dc
dt
=
N R2
A ∆C
(η) (h)
• where,
- dc/ dt = rate of the absorption.
- N = number of pores
- R = radius of pores
- ∆C = concentration gradient
- η = viscosity of fluid in the pores
- h = thickness of the membrane
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3. ION-PAIR TRANSPORT
• Responsible for absorption of compounds which ionizes at all pH values.
e.g. quaternary ammonium, sulphonic acids.
• Ionized moieties forms neutral complexes with endogenous ions which
have both the required lipophilicity and aqueous solubility for passive
diffusion.
• E.g. Propranolol, a basic drug that forms an ion pair with oleic acid and is
absorbed by this mechanism.
4. IONIC OR ELECTROCHEMICAL DIFFUSION
• Charge on membrane influences the permeation of drugs.
• Molecular forms of solutes are unaffected by the membrane charge and
permeate faster than ionic forms.
• The permeation of anions and cations is also influenced by pH. Once
inside the membrane, the cations are attached to negatively charged
intracellular membrane, thus giving rise to an electrical gradient.
• If the same drug is moving from a higher to lower concentration, i.e.
moving down the electrical gradient, the phenomenon is known as
electrochemical diffusion.
• Thus, at a given pH, the rate of permeation may be as follows:
- Unionized molecule > anions > cations.
5. CARRIER MEDIATED TRANSPORT
• Involves a carrier which reversibly binds to the solute molecules and
forms a solute-carrier complex.
• This molecule transverse across the membrane to the other side and
dissociates, yielding the solute molecule.
• The carrier then returns to the original site to accept a new molecule.
• There are two type of carrier mediated transport system.
- Facilitated diffusion - Active transport
I. FACILITATED DIFFUSION
• Facilitated diffusion is a form of carrier transport that does not require
the expenditure of cellular energy.
• Carriers are numerous in number and are found dissolved in cell
membrane.
• The driving force is concentration gradient, particles move from a region
of high conc. to low concentration.
• The transport is aided by integral membrane proteins.
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• Facilitated diffusion mediates the absorption of some simple sugars,
steroids, amino acids and pyrimidines from the small intestine and their
subsequent transfer across cell membranes.
II. ACTIVE TRANSPORT
• Requires energy, which is provided by hydrolysis of ATP for
transportation.
• More commonly, metabolic energy is provided by the active transport of
Na+
or is dependent on the electrochemical gradient produced by the
sodium pump, Na+
/K+
ATPase (secondary active transport).
• PRIMARY ACTIVE TRANSPORT
- Direct ATP requirement
- The process transfers only one ion or molecule and only in one
direction. Hence, called as uniport.
- E.g. Absorption of glucose.
- ABC (ATP Binding Cassette) transporters
• SECONDARY ACTIVE TRANSPORT
- No direct requirement of ATP
- The energy required in transporting an ion aids transport of
another ion or molecule (co-transport or coupled transport) either
in the same direction or opposite direction.
- 2 types:
▪ Symport (co-transport)
▪ Antiport (counter transport)
6. ENDOCYTOSIS
• It is a process in which cell absorbs molecules by engulfing them.
• Also termed as vesicular transport.
• It occurs by 3 mechanisms:
- Phagocytosis
- Pinocytosis
- Transcytosis
I. PHAGOCYTOSIS
• Phagocytosis refers to the engulfment of larger particles or
macromolecules, generally by macrophages.
II. PINOCYTOSIS
• It is a form of endocytosis in which small particles are brought to the
cell, forming an invagination.
• These small particles are suspended in small vesicles.
• It requires energy in the form of ATP.
13
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• It works as phagocytosis, the only difference being, it is non-specific in
the substances it transports.
• This process is important in the absorption of oil soluble vitamins & in
the uptake of nutrients.
III. TRANSCYTOSIS
• It is the process through which various macromolecules are transferred
across the cell membrane.
• They are captured in vesicles, on one side of the cell and the endocytic
vesicle is transferred from one extracellular compartment to another.
• Generally used for the transfer of IgA and insulin.
FACTORS AFFECTING DRUG ABSORPTION
1. Pharmaceutical factors
A. Physicochemical factors
B. Formulation factors
2. Patient related factors
A. Physiological factor
B. Clinical factor
1. PHARMACEUTICAL FACTORS
A. PHYSICO -CHEMICAL FACTORS
• Drug solubility and
dissolution rate.
• Particle size & effective
surface area.
• Polymorphism & amorphism.
• Salt form of the drug
• Lipophilicity of the drug
• pKa of the drug & pH
• Drug stability
I. DRUG SOLUBILITY AND DISSOLUTION RATE
• Rate determining process in the absorption of orally administered drugs
are:
- Rate of dissolution
- Rate of drug permeation through the bio-membrane.
• Hydrophobic: Rate Determination Step → Dissolution
- E.g: Griseofulvin, spironolactone
• Hydrophilic: Rate Determination Step → Permeation rate limited.
- E.g: Cromolyn sodium or neomycin
II. PARTICLE SIZE AND EFFECTIVE SURFACE AREA
• Particle size and surface area of a solid drugs are inversely related to
each other.
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GM Hamad
• Hydrophobic drugs → micronization → greater surface area → rapid
dissolution.
- E.g: griseofulvin, spironolactone
• Some of the Hydrophobic drugs → micronization → decrease in effective
surface area → fall in dissolution rate.
- Causes
▪ Adsorption of air to surface
▪ Particle reaggregation
▪ Surface charge
- E.g: aspirin, phenacetin
- In that case add Surfactants: tween 80, hydrophilic diluents: PEG,
PVP, Dextrose.
III. POLYMORPHISM AND AMORPHISM
• POLYMORPHISM
- A substance exists in more than one crystalline form, the different
forms are designated as polymorphs and the phenomenon as
polymorphism.
▪ Enantiotropic polymorph: Sulphur
▪ Monotropic polymorph: glyceryl stearate
- Depending on their relative stability, one of the several
polymorphic forms will be physically more stable than the others.
- Stable polymorphs
▪ Highest MP
▪ Lowest energy
state
▪ Least aqueous
solubility
- Metastable polymorphs
▪ Low MP
▪ Higher energy
state
▪ High aqueous
solubility
- E.g. The vitamin riboflavin exists in several polymorphic forms,
and these have a 20-fold range in aqueous solubility.
• AMORPHISM
- These drugs can exist with no internal crystal structure.
- Such drug represents the highest energy state and can be
considered as super cooled liquids and thus have greater
solubility. E.g. Novobiocin.
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- Thus, the order of dissolution and hence absorption for different
solid dosage forms is amorphous > meta-stable > stable.
IV. SALT FORM OF THE DRUG
• Salt of weak acid and weak bases have much higher aqueous solubility
than the free acid or base.
• Therefore, if the drug can be given as a salt, the solubility can be
increased, and the dissolution thus can be improved.
V. DRUG pKa, LIPOPHILICITY AND GI pH
pH PARTITION THEORY
• Explains influences of GI pH drug pKa on the extent of drug transfer or
drug absorption (Ka – absorption rate constant).
• The process of absorption of drug compounds of molecular weight
greater than 100 Daltons transported across the bio-membrane by
passive diffusion depend upon the following factors:
- Dissociation constant of the drug i.e. pKa of the drug
- Lipid solubility of the unionized drug i.e. Ko/w
- pH at the absorption site
• The amount of drug that exist in unionized form is a function of
dissociation constant(pKa) of the drug and pH of the fluid at the
absorption site.
• PKa of the drug
- Dissociation or ionization constant:
▪ pH at which half of the substance is ionized and half is
unionized.
• pH of medium
- Affects ionization of drugs:
▪ Weak acids → best absorbed in stomach.
▪ Weak bases → best absorbed in intestine.
• pH-partition Hypothesis
- Unionized Drug: Higher Absorption
- Ionized Drug: Low Absorption
• FOR WEAK ACIDS
% Drug Ionized =
10pH
− pKa
1 + 10pH − pKa
X 100
• FOR WEAK BASES
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% Drug Ionized =
10pKa
− pH
1 + 10pKa − pH
X 100
PREDICTION BASED ON THEORY
Drugs PKa PH / Site of absorption
For Acidic Drugs
Very weak acids
E.g. pentobarbital,
Hexobarbital
> 8
Unionized at all pH values;
Absorbed along the entire
length of GIT.
Moderately weak acids
E.g. aspirin, Ibuprofen
2.5 – 7.5
Unionized in gastric pH and
ionized in intestinal pH; better
absorption from stomach.
Stronger acids
E.g. disodium
cromoglycate
< 2.0
Ionized at all pH values; Poorly
absorbed from GIT.
For Basic Drugs
Very weak bases
E.g. theophylline,
Caffeine
< 5.0
Unionized at all pH values;
Absorbed along entire GIT.
Moderately weak bases
E.g. codeine
5 – 11
Ionized at gastric pH,
unionized
at intestinal pH; better
absorption from intestine.
Stronger bases
E.g. guanethidine
> 11
Ionized at all pH values; Poorly
absorbed from GIT.
VI. LIPOPHILICITY
• Only unionized drug having sufficient lipid solubility is absorbed into
systemic circulation.
• So, drug should have sufficient aqueous solubility to dissolve in the fluids
at the absorption site and lipid solubility high enough to facilitate the
partitioning of the drug in lipoidal membrane and into systemic
circulation.
VII. DRUG PERMEABILITY
• Three major drug properties which affects drug permeability:
- Lipophilicity
- Polarity of the drug
- Molecular size of the drug
VIII. DRUG STABILITY
• Two major stability problems are:
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GM Hamad
- Degradation of the drug into inactive form.
- Interaction with one or more component either of the dosage
form or those present in the GIT to form a complex that is poorly
soluble.
B. FORMULATION FACTORS
• Disintegration time
• Manufacturing variables
• Different Oral Dosage forms
• Pharmaceutical ingredients/
Excipients
• Product age and storage
condition
I. DISINTEGRATION TIME
• It Is of particular importance in case of solid dosage forms like tablets
and capsules.
• Rapid disintegration is important in the therapeutic success of solid
dosage form.
• Sugar coated tablets have long disintegration time (DT).
• DT is directly related to the amount of binder present and the
compression force of a tablet.
• After disintegration, granules deaggregate into tiny particles →
dissolution faster.
II. MANUFACTURING VARIABLES
a) METHOD OF GRANULATION
• Wet granulation was thought to be the most conventional technique.
• Direct compressed tablets dissolve faster.
• Agglomerative phase of communition → superior product.
b) COMPRESSION FORCE
• Higher compression force → increased density and hardness →
decreased porosity and penetrability → reduced wettability → in turn
decreased DR.
• Also causes deformation, crushing → increased effective surface area →
increased dissolution rate (DR).
c) INTENSITY OF PACKING OF CAPSULE CONTENTS
• Tightly filled capsules-diffusion of GI fluids → high pressure → rapid
bursting and dissolution of contents.
• Opposite also possible → Poor drug release due to decreased pore size
and poor penetrability of GI fluids.
III. ABSORPTION OF DIFFERENT ORAL DOSAGE FORMS
• Different Types
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GM Hamad
- Solution
- Suspension
- Tablets
- Capsules
- Enteric Coated Tablet
- Powders
• Order of absorption
Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated
Tablets > Enteric Coated Tablet > Sustain Release Tablet
a) SOLUTION
• Aqueous solutions, syrups, elixirs, and emulsions do not present a
dissolution problem and generally result in fast and often complete
absorption as compared to solid dosage forms.
b) SOLID SOLUTIONS
• The solid solution is a formulation in which drug is trapped as a solid
solution or monomolecular dispersion in a water-soluble matrix.
Although the solid solution is an attractive approach to increase drug
absorption, only one drug, griseofulvin, is currently marketed in this
form.
c) SUSPENSIONS
• A drug in a suspension is in solid form but is finely divided and has a
large surface area. Drug particles can diffuse readily between the
stomach and small intestine so that absorption is relatively insensitive to
stomach emptying rate.
• Adjusting the dose to a patient’s needs is easier with solutions and
suspensions than with solid dosage forms. Liquid dosage forms,
therefore, have several practical advantages besides simple dissolution
rate.
• However, they also have some disadvantages, including greater bulk,
difficulty in handling, and perhaps reduced stability.
d) TABLETS AND CAPSULES
• These formulations differ from each other in that material in capsules is
less impacted than in compressed tablets. Once a capsule dissolve, the
contents generally disperse quickly. The capsule material, although
water soluble, can impede drug dissolution by interacting with the drug,
but this is uncommon.
• Tablets generally disintegrate in stages, first into granules and then into
primary particles. As particle size decreases, dissolution rate increases
due to increased surface area.
IV. PHARMACEUTICAL INGREDIENTS/EXCIPIENTS
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GM Hamad
• More the number of excipients in dosage form, more complex it is and
greater the potential for absorption and bioavailability problems.
• Changing an excipient from calcium sulfate to lactose and increasing the
proportion of magnesium silicate, increases the activity of oral
phenytoin.
• Absorption of tetracycline from capsules is reduced by calcium
phosphate due to complexation.
• Most of these types of interactions were reported some time ago and
are unlikely to occur in the current environment of rigorous testing of
new dosage forms and formulations.
• Excipients commonly used:
- Vehicle
- Diluents
- Binders & granulating
agent
- Disintegrants
- Lubricants
- Suspending
agents/viscosity agent
- Surfactants
- Bile salts
- Colorants
V. PRODUCT AGE AND STORAGE CONDITIONS
• Aging and alteration in storage condition changes the physiochemical
properties of a drug which adversely affects bioavailability.
• During storage
- Metastable form → Stable form
- Change in particle size
- Tablet → harden / soften
• E.g.
- Prednisone tablet containing lactose as a filler, high temp and high
humidity resulted in harder tablet that disintegrated and dissolve
slowly.
2. PATIENT RELATED FACTORS
A. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION
I. MEMBRANE PHYSIOLOGY
• Nature of Cell Membrane
• Transport Processes
II. GASTERO-INTESTINAL PHYSIOLOGY
a) GASTRIC EMPTYING RATE
• Anatomically, a swallowed drug rapidly reaches the stomach.
20
GM Hamad
• Eventually, the stomach empties its contents into the small intestine.
Because the duodenum has the greatest capacity for the absorption of
drugs from the GI tract, a delay in the gastric emptying time for the drug
to reach the duodenum will slow the rate and possibly the extent of drug
absorption, thereby prolonging the onset time for the drug.
• Some drugs, such as penicillin, are unstable in acid and decompose if
stomach emptying is delayed. Other drugs, such as aspirin, may irritate
the gastric mucosa during prolonged contact.
• Gastric emptying rate is faster in case of solution & suspensions than
solid and non-disintegrating dosage forms.
• Factors that influence gastric emptying rate are:
- Volume of meal
- Composition of meal
- Physical state and
viscosity of meal
- Temperature of meal
- Gastrointestinal pH
- Electrolyte and osmotic
pressure
- Body posture
- Emotional state
b) INTESTINAL MOTILITY
• Normal peristaltic movements mix the contents of the duodenum,
bringing the drug particles into intimate contact with the intestinal
mucosal cells.
• The drug must have a sufficient time (residence time) at the absorption
site for optimum absorption. In the case of high motility in the intestinal
tract, as in diarrhea, the drug has a very brief residence time and less
opportunity for adequate absorption.
c) DRUG STABILITY IN GIT
• Metabolism or degradation by enzymes or chemical hydrolysis may
adversely affect the drug absorption and thus reduces bioavailability.
• Destruction in gastric acid.
• Generally, a problem with orally administered drugs.
d) INTESTINAL TRANSIT
• Long intestinal transit time is desirable for complete absorption of drug
e.g. for enteric coated formulation and for drugs absorbed from specific
sites in the intestine.
• Peristaltic contraction promotes drug absorption by increasing the drug
membrane contact and by enhancing dissolution especially of poorly
soluble drugs.
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GM Hamad
• Influenced by food, disease and drugs. e.g. metoclopramide which
promotes intestinal transit and thus enhance absorption of rapidly
soluble drugs while anticholinergic retards intestinal transit and
promotes the absorption of poorly soluble drugs.
e) BLOOD FLOW TO GIT
• Once the drug is absorbed from the small intestine, it enters via the
mesenteric vessels to the hepatic-portal vein and the liver prior to
reaching the systemic circulation. Any decrease in mesenteric blood
flow, as in the case of congestive heart failure, will decrease the rate of
drug removal from the intestinal tract, thereby reducing the rate of drug
bioavailability.
• GIT has higher perfusion rate because it is extensively supplied by blood
capillary network.
• Therefore, help in maintaining sink conditions and concentration
gradient for drug absorption by rapidly removing of drug from site of
action.
• Blood flow is important for actively absorption of drugs.
• Highly permeable drugs or drugs that absorbed through pores –GI
perfusion is rate limiting while the drugs with poor permeability GI
perfusion is not important.
• Perfusion increases after meals and persist for few hours, but absorption
is not affected.
f) EFFECT OF FOOD
• The presence of food in the GI tract can affect the bioavailability of the
drug from an oral drug product.
• Digested foods contain amino acids, fatty acids, and many nutrients that
may affect intestinal pH and solubility of drugs. The effects of food are
not always predictable and can have clinically significant consequences.
Some effects of food on the bioavailability of a drug from a drug product
include:
- Delay in gastric emptying
- Stimulation of bile flow
- A change in the pH of GI tract
- An increase in splanchnic blood flow
- A changed luminal metabolism of the drug substance
- Physical or chemical interaction of the meal with the drug product
or drug substance.
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GM Hamad
• The absorption of some antibiotics, such as penicillin and tetracycline, is
decreased with food, whereas other drugs, particularly lipid-soluble
drugs such as griseofulvin and metaxalone, are better absorbed when
given with food containing a high fat content.
• Propranolol plasma concentrations are larger after food than in fasted
subjects. This may be an interaction with the components of food.
III. AGE
• In infants, the gastric pH is high and intestinal surface and blood flow to
the GIT is low resulting in altered absorption pattern in comparison to
adults.
• In elderly persons, causes of impaired drug absorption include altered
gastric emptying, decreased intestinal surface area and GI blood flow,
higher incidents of achlorhydria and bacterial overgrowth in small
intestine.
B. CLINICAL FACTORS
I. DISEASE STATE
• Several disease state may influence the rate and extent of drug
absorption.
• Three major classes of disease may influence bioavailability of drug.
- GI diseases
- CVS diseases
- Hepatic diseases
a) GI DISEASES
• GI Infections
- Celiac diseases: Characterized by destruction of villi and microvilli.
Abnormalities associated with this disease are increased gastric
emptying rate and GI permeability, altered intestinal drug
metabolism.
• Crohn’s disease
- Altered gut transit time and decreased gut surface area and
intestinal transit rate.
• GI surgery
- Gastrectomy may cause drug dumping in intestine, osmotic
diarrhea and reduce intestinal transit time.
b) CVS DISEASES
• In CVS diseases blood flow to GIT decrease causing decreased drug
absorption.
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GM Hamad
c) HEPATIC DISEASES
• Disorders like hepatic cirrhosis influences bioavailability of drugs which
undergoes first pass metabolism.
II. DRUGS
a) ANTICHOLINERGIC
• Anticholinergic drugs in general may reduce stomach acid secretion
Propantheline bromide is an anticholinergic drug that may slow stomach
emptying and motility of the small intestine. Slower stomach emptying
may cause delay in drug absorption
b) METOCLOPRAMIDE
• Metoclopramide is a drug that stimulates stomach contraction, relaxes
the pyloric sphincter, and, in general, increases intestinal peristalsis,
which may reduce the effective time for the absorption of some drugs.
c) ANTACIDS
• Antacids containing aluminum, calcium, or magnesium may complex
with drugs such as tetracycline, ciprofloxacin, and indinavir, resulting in a
decrease in drug absorption.
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GM Hamad
BIOLOGICAL HALF LIFE & VOLUME OF
DISTRIBUTION
HALF LIFE
• The time needed to decrease the body drug level by one half of its initial
level. If the concentration is reduced due to a physiological process, i.e.,
biotransformation then, this half life is called as elimination or biological
half life.
• The half life is the time required for the body to eliminate one half of the
drug which it contains. The elimination half life is a function of both, the
clearance and the volume of distribution of the drug. It is the
characteristic of exponential decay where the time required for a given
fraction of drug to disappear is always the same, regardless of the time
or concentration at which one begins measurements.
• The biological half life is not the time for the response to decline by 50%,
since the requirement for a threshold concentration, latency of drug
response and other factors cause a non-parallelism between blood
concentration and pharmacological response intensity.
• The half life is used to determine the time required for the body to
eliminate by metabolizing, or excretion or by both, one half of the initial
concentration of drug in blood.
OTHER TYPES OF HALF LIFE
• Besides the elimination half life, the other types of half life are as
follows:
ABSORPTION HALF LIFE
• It is the time to reduce drug concentration at absorption site due to
absorption by one half of its initial concentration.
DISTRIBUTION HALF LIFE
• The time required to reduce concentration of drug to half of its initial
concentration due to the distribution of drug is called as distribution half
life.
PHYSICAL HALF LIFE
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GM Hamad
• This half life pertains to the radiopharmaceuticals. Physical half life is the
time to decrease the concentration of a substance to half due to physical
decay. For instance, the radiopharmaceutical decays physically and the
time at which its concentration is reduced to half of its initial
concentration is the physical half life.
EFFECTIVE HALF LIFE
• When a radiopharmaceutical is administered, its concentration decays
due to its physical disintegration as well as due to its biotransformation.
Effective half life combines both the elimination half life and the physical
half life of a radiopharmaceutical.
ZERO AND FIRST ORDER HALF LIFE
• Drug concentration may decay by two modes, first order half life or by
zero order half life.
FIRST ORDER HALF LIFE
• Half life of the first order process is a constant for a given rate process
hence the half life is the time required [C]t (concentration at time t) to
become equal to one half of [C]0 (the initial value at zero time). The first
order half life can be calculated by the formula:
t½ =
0.693
k
• This formula has been derived from the equation of the graph to
describe the first order kinetics. The basis for this equation is Y = mx + b,
where Y is the concentration, m is the slope (or rate constant) of the
curve and b is the y-intercept.
• Log natural (Ln) is included because the blood level time curve is a
straight line on the graph between Ln of concentration versus time.
Ln[C]t − Ln[C]0 = −kt
This equation can be arranged in the following several ways
−Ln[C]t = −kt + Ln[C]0 ⇛ −Ln
[C]t
[C]0
= kt ⇛ Ln
[C]0
[C]t
= kt
• By definition half life is the time when the concentration is half of the
initial concentration, thus, at this time, in equation, the [C]t becomes
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GM Hamad
½ [C]0 and t as t½.
Ln
[C]0
1
2
[C]0
= kt½
Rearranging the above equation yields the following equation.
Ln
2[C]0
[C]0
= kt½ ⇛ Ln
2
k
= t½
• This equation represents one of the ways to calculate the first order half
life using the rate constant determined from a first order graph of the
data. A drug being eliminated by a first order process will have a half life
which is constant and independent of the initial concentration or dose of
the drug.
ZERO ORDER HALF LIFE
• The half life of zero order process is not like that discussed for the first
order process.
• Applying the definition of half life to the zero-order process, equation
yields as:
[C]t = −kt + [C]0
• At half life, the [C]t in equation becomes ½[C]0 and the t as t½, thus the
above equation for zero order becomes as following.
[C]0
2
− [C]0 = −kt½ ⇛ −
[C]0
2k
= −t½ ⇛ t½ =
0.5[C]0
k
• Where C0 is the initial concentration, k is the rate constant for the zero-
order process. The equation indicates that the half life is not independent
of the initial concentration. Factually, lager the initial concentration, the
greater is the half-life. The difference can be used to distinguish between
zero and first order process by varying the initial concentration (or order)
and measuring the resulting half life.
METHOD OF DETERMINATION
1. Direct graphical method:
- Half life of a drug can be estimated by direct reading the time
needed for concentration to decrease by one half from any point
on the log concentration time plot.
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GM Hamad
2. From the slope of the terminal log concentration time curve:
- The slope of the curve is the elimination rate constant. Using the
formula of first order half life, half life can be calculated.
3. Calculation from urine data:
- Half life is also calculated from the urine data assuming that the
renal clearance of drug is constant, the excretion rate parallels the
plasma concentration. The half life can be calculated by urine
concentration data. But practically, urine concentration data gives
usually poor estimate due to incomplete bladder emptying and
inability to collect samples frequently.
RELATIONSHIP OF ELIMINATION HALF LIFE WITH CLEARANCE, VOLUME OF
DISTRIBUTION
• The clearance and volume of distribution are the two independent
pharmacokinetic parameters which determine elimination half life and
thus, the half life. These two are the dependent parameters.
C𝑙 = K x Vd ⇛
C𝑙
Vd
= k ⇛
0.693
t½
SIGNIFICANCE OF HALF LIFE
1. Reflects the rate of drug elimination, similar to the elimination rate
constant. Drug that have a short half life (i.e., having larger elimination
rate constant) are readily eliminated from the body.
2. Half life is used in deciding the appropriate dosage regimen. Drugs with
shorter half life require frequent dosing during multiple administration.
3. It gives the estimate of the rate of drug removal from the body.
4. It indicates the efficiency of the elimination process. Thus, change in half
life will reflect change in elimination organ functions such as liver
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GM Hamad
biotransformation or the excretion in kidney. It is thus, a prime measure
for the dosage adjustment in disease status.
5. A drug with brief half life requires more frequent dosage that the drug
with long half life.
6. The drug having half-life between 3 to 4 hours are the good candidates
for control release formulations.
7. Drugs reach to steady state concentration in approximately 5 half lives.
8. A drug is completely eliminated after 10 half life and usually negligible
within 7 half lives.
9. Provides the basis for classification of the drugs having ultra-fast, slow
and very slowly disposition drugs. The ultra-fast disposition (UFD) drugs
has half life of less than 1-hour, slow disposition (SD) drugs have half life
of 8-24 hours and that very slow disposition (VSD) drugs have the half
life of more than 24 hours.
FACTORS AFFECTING HALF LIFE
• Half life of a drug is affected by any factor which modifies the drug
metabolism and excretion. The factors can be categorized into patient
related, drug related and combinedly related to the drug as well as to
the patient. Patient related factors include age, genetic, renal
insufficiencies, hepatic insufficiencies, urine pH, gender, nutritional
status, emotional status, hormonal level, body temperature, volume of
distribution, etc.
• Factors related to drug include co-administered drug-drug interaction,
inhibition of drug metabolism, stimulation of drug metabolism via
increased enzyme activity or via enzyme induction, therapy duration
(enzyme exhausted).
COMBINED PATIENT AND DRUG RELATED FACTORS
• Combined patient and drug related factors include the pKa of acidic or
basic drugs, affinity for protein binding, tissue storage, volume of
distribution.
RENAL MALFUNCTION
• The renal clearance is altered if there is any disease, malfunctioning or
insufficiencies of kidney.
• When renal clearance decreases, the half life is increased and vice versa.
HEPATIC DISEASE
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GM Hamad
• Liver is the site of metabolism for most of the drugs. When the liver is
not functioning properly, the rate of drug elimination will be decreased
due to a decreased metabolism leading to increase in half life of the
drug.
URINARY pH
• pH changes leads to altered rate of drug excretion and kidney
reabsorption of the drug. Basic drugs are rapidly excreted through acidic
urine and vice versa. This of course will affect the half life.
AGE
• As rate of metabolism are different in various stage of human age, the
half life obviously varies in different age groups. In children, liver is not
well developed so the metabolism rate is slow. In elder patients, the
system gets exhausted and thus the rate is slow. GFR is also gradually
decreased after the age of 30 years.
AFFINITY FOR PROTEIN BINDING
• Customarily, the drug bound with protein is not available for drug
metabolism and excretion thus leading to an increased half life.
However, drugs can be categorized into restrictively cleared and non-
restrictively cleared drugs.
• The restrictive cleared drugs are also known as binding sensitive drugs.
The bound drugs not able to diffuse through cell membrane, and thus
not able to reach site of metabolism and excretion. Thus for such drugs,
increase in the free drug concentration in the blood will make more drug
available for hepatic extraction as well as for renal excretion.
• Non-restrictively cleared drugs are also known as binding-insensitive
drugs. These drugs are extracted by the liver with greater rate regardless
of bound to protein or free. The elimination half life of such drug is not
significantly affected by a change in the degree of protein binding. The
drug is removed from the plasma binding sites during the circulation
through the liver by inducing a conformation change in the protein,
weakening the process of binding and subjecting the drug to
metabolism. The drugs activity secreted though the renal route are
binding insensitive.
TISSUE STORAGE
30
GM Hamad
• Certain drugs have an affinity for adipose tissue and thus are stored for a
prolonged time period leading to an increased half life.
CO-ADMINISTRATION OF DRUG AND DRUG INTERACTION
• Co-administrated drugs may alter the half life of one another drug by:
- Competing for protein binding i.e., warfarin and phenylbutazone.
- Competing for metabolizing enzyme if both are metabolized by
the same enzyme
- Altering the urinary pH
- Enzyme inhibition - increases the half life
- Enzyme induction - decrease the half life.
GENETIC FACTORS
• The genetic factors contribute substantially to the larger difference
among the individuals for fate of drug metabolism and clearance of
drug. Thus, half life of drug is affected by genetic variations. Some
individuals are slow acetylators while others are fast acetylators.
VOLUME OF DISTRIBUTION
• Half life is the function of both the clearance and the volume of
distribution of drug may have large clearance but still have a long half
life due to increase value of the volume of distribution.
VOLUME OF DISTRIBUTION (Vd)
• Volume of distribution is defined as the apparent volume available for
the distribution of a drug in body. This parameter indicates the apparent
space as volume in body available to contain drug.
• Since the values of Vd does not have a true physiologic meaning in terms
of an anatomic space, the term “apparent” is used with Vd as prefix. The
Vd represents a volume that must be considered in estimating the
amount of drug in body from the concentration of drug found in the
sampling compartment, i.e. blood.
• Since the drug is not distributed equally in all tissues of the body
(compartments) due to drug’s different affinities to different tissues, the
volume of distribution does not represent a real volume rather
represents a hypothetical volume. This volume relates the amount of
drug in the body to the plasma concentration by the equation:
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GM Hamad
Vd =
Db
Cp
- Where, Db is the drug in body and Cp is the concentration in
plasma.
• Though the Vd is hypothetical, yet it is influenced by the
physicochemical properties and the affinity of drugs to the blood and
tissues. The drug lipid solubility which dictates the affinity of drug to
tissues and the protein binding, affect Vd.
• Vd is an independent pharmacokinetic parameter which does not
depends on the other pharmacokinetic parameters. Vd provides an
estimate of the drug which does not appear in the plasma or distributed
at tissue level. A very high Vd reflects binding of drug with the tissue
proteins.
RELATIONSHIP OF VD WITH OTHER PHARMACOKINETIC PARAMETERS
• The following equation shows the relationship of Vd with other
pharmacokinetic parameters, such as elimination rate constant and the
clearance.
C𝑙 = k x Vd
SIGNIFICANCE OF Vd
• The Vd is used to calculate a dose of drug required to achieve certain
blood concentration (called as the target concentration and abbreviated
as CT) as:
Dose = CT x Vd
• The volume of distribution is a distribution parameter which indicates
the extent of distribution. Based on its obtained values, the extent of
drug distribution can be classified as:
- The widely distributed drugs which show volume of distribution
greater than 0.7 L/Kg.
- The moderately distributed drug which demonstrates values of
the volume of distribution between 0.3-0.7 L/Kg.
- Limited distributed drugs having the volume of distribution lesser
than 0.3 L/Kg.
• As has been mentioned that the Vd is not a true physiologic volume,
most of the drugs have an apparent volume of distribution smaller than,
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GM Hamad
equal to or several times more than the body mass. It depends on the
initial plasma concentration.
• Vd is a useful parameter in considering the relative amount of drug in
the vascular and in the extravascular tissues.
• Magnitude of the apparent Vd is a useful indicator for the amount of
drug outside the sampling compartment which is usually blood. The
volume of distribution at steady-state (Vd(ss)) is important for
determining the relevance of changes in the extent of distribution of
drug in the presence of diseases.
ALTERED Vd
• For each drug, the apparent Vd is a constant. In certain pathologic cases
however, the Vd for the drug may be altered if the distribution of the
drug is changed due to the change in the total body water and total
extracellular water. If these increases, (as in the case of edematous
condition), a very larger Vd results for a drug with more water solubility.
EXCESSIVELY LARGER Vd
• Drugs may exhibit very large values of Vd which exceed all the volumes
available in the body, e.g., chloroquine Vd is about 115 L/ kg. Such drugs
show concentration of drug specifically in one or more tissues.
Chloroquine concentrates in liver 1000 times more than in plasma.
• Even wide range of Vd values are expected for the drugs exhibit a non-
uniform distribution in the body with variations due to difference in
their passing through membranes and their lipid/water solubility.
• The highest concentrations of drugs are often present in the kidney,
liver, and intestine which usually reflect the amounts of drug being
excreted.
LARGER Vd
• A larger Vd occurs if the drug is extensively distributed in peripheral
tissues and organs and resulting into a smaller inter-vascular
concentration. This means that the drug with a larger apparent Vd are
more concentrated in extravascular tissues and less concentrated
intravascularly. A Vd between 30 and 50 liters, corresponds to drug
distribution in the total body water.
• Binding of the drug with peripheral tissue or its proteins, results into an
increased Vd. The protein bound drugs showing larger Vd when
33
GM Hamad
displaced from the protein, do not show any clinically relevant
consequence.
SMALLER Vd
• If a drug is highly bound to plasma proteins, or remains in the vascular
regions, it will result in a smaller apparent Vd. A value of Vd in the range
of 3-5 liter (in an adult) would indicate that the drug is in the vascular
compartment since this is the value of plasma volume.
• For polar drugs with low lipid solubility, the apparent Vd is generally
small. Protein bound drugs having smaller Vd, produce
pharmacodynamic effects when displaced from plasma protein.
• In two compartment model, Vdss reflects the true distribution volume
occupied by the plasma and the tissue pool when steady state is
achieved. This volume is used to calculate the loading drug dose
necessary to upload the body to a desired plasma drug concentration.
CALCULATION OF VOLUME OF DISTRIBUTION
• The volume of distribution after extravascular administration is
calculated as Vd (area) by the following equation.
Vd(area) =
Dose
AUC . β
- Where, AUC is total area under the blood level time curve, beta is
rate of elimination.
• The Vd(ss) is the volume of distribution after IV administration and it
represent the volume in which a drug appears to be distributed during
steady-state if drug existed throughout the volume at the same
concentration as in the measured fluid. The Vd(ss) is generally calculated
by non-compartmental approach as:
Vd(ss) =
DoseIV . AUMC
(AUC)2
- Where AUC is the total area under the curve and AUMC is the area
under the first moment of the plasma concentration-time curve.
The value of Vd(ss) is generally smaller than the Vd area.
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GM Hamad
DRUG CLEARANCE
INTRODUCTION
• Synonyms: Systemic clearance, body clearance, total clearance.
• Total clearance represents sum of clearances by the various organs that
contribute to elimination of drug.
C𝑙Total = C𝑙Renal + C𝑙Hepatic + C𝑙Lungs
• Clearance describes the process of drug elimination from the body or
from a single organ without identifying the individual processes
involved.
• Clearance can be defined as “The volume of fluid cleared of drug from
the body per unit time.”
• Clearance is a proportionality constant describing a relationship
between rate of elimination (as amount per unit time) at a given time
and its corresponding concentration in fluid at that time.
• It may be regarded as, “the volume of blood or plasma (depending upon
the fluid used for drug assay) from which the drug appears to be
removed per unit of time to account for its elimination.”
• Example: clearance considers that a certain portion or fraction (percent)
of the distribution volume is cleared of drug over a given time period.
• Clearance is a pharmacokinetic parameter that describes drug
elimination from a hypothetical well stirred compartment containing
uniform drug distribution.
• For first order elimination process, clearance is constant. Clearance
applies to all elimination rate processes, regardless of the mechanisms
for elimination. It may have values that are not physiological.
• Unit: The unit of clearance are milliliters per minute (ml/min, ml/min.Kg)
or liters per hour (L/h, L/h.Kg).
IMPORTANCE OF CLEARANCE
• Clearance is the one parameter that determines the maintenance dose
rate required to achieve a desired plasma concentration.
Dosing rate = clearance x desired plasma concentration
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GM Hamad
MECHANISIM OF CLEARANCE
• Renal excretion
• Hepatic excretion
• Minor clearance through lungs and skin.
RENAL EXCRETION
• Renal excretion is the major route of elimination for many drugs. For
example, water soluble and low molecular weight drugs, or the drugs
that are slowly bio-transformed by the liver.
• Drug excretion from the kidney involves combination of the following:
- Glomerular filtration
- Active tubular secretion
- Tubular reabsorption
HEPATIC CLEARANCE
• Hepatic clearance is the volume of blood that perfuses the liver which is
cleared of drug per unit time.
• Hepatic clearance involve Biotransformation or Drug Metabolism (Phase
I and Phase II).
CLEARANCE MODELS
• Model Independent
• Model dependent or Compartment Model
• Physiologic Model
MODEL INDEPENDENT
• This is a non-compartmental approach used to calculate Clearance. This
model does not require any assumption for a specific compartment
model.
• Therefore, Clearance can be determined directly from the Plasma-Time
concentration curve using:
𝐶𝑙 = ∫
𝐷0
𝐶 𝑝 𝑑𝑡
∞
0
• Since there is no compartment considered, therefore, [AUC]0
∞
=
∫ 𝐶 𝑝 𝑑𝑡
∞
0
, Replacing this in the above equation gives:
𝐶𝑙 =
𝐷0
[AUC]0
∞
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GM Hamad
MODEL DEPENDENT OR COMPARTMENTAL MODEL
• Model Dependent considers compartmental approach and the clearance
is calculated by assuming volume of distribution and elimination rate
constant.
C𝑙T = 𝑘V 𝐷
PHYSIOLOGIC MODEL
• This model is organ specific. Clearance may be defined as the fraction of
blood volume containing drug that flows through the organ and is
eliminated of drug per unit time. OR
• Clearance is the product of the blood flow (Q) to the organ and the
extraction ratio (ER).
C𝑙Organ = Q(ER)
• If the drug concentration in the blood (Ca) entering the organ is greater
than the drug concentration of blood (Cv) leaving the organ, then some
of the drug has been extracted by the organ.
• The ER is Ca – Cv divided by the entering drug concentration (Ca), as
shown:
ER =
Ca − Cv
Ca
Substituting in the previous equation
C𝑙Organ = Q (
Ca − Cv
Ca
)
CALCULATION OF CLEARANCE
• Body clearance (ClB) after E/V route is:
C𝑙B =
𝐹 . 𝐷𝑜𝑠𝑒
𝐴𝑈𝐶
• For ClB after IV route the fraction of dose absorbed (F) is not included in
equation:
C𝑙B =
𝐷𝑜𝑠𝑒
𝐴𝑈𝐶
• For ClB after steady state IV infusion:
C𝑙B =
k0
Css
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GM Hamad
• If volume of distribution by area calculated from terminal curve (Vdarea)
and rate of elimination (Ke) is known, then ClB is:
C𝑙B = 𝑉𝑑 𝑎𝑟𝑒𝑎 ⨯ ke
RELATIONSHIP OF CLEARANCE WITH HALF-LIFE
• If we know the Clearance, we can determine Half-Life (t½) of a drug
through a simple relation:
C𝑙T = k ⨯ Vd
k =
0.693
t½
Therefore, by substitution
C𝑙T =
0.693 𝑉𝑑
𝑡1/2
APPLICATIONS OF CLEARANCE
1. The volume concept is simple and convenient because all drugs are
dissolved and distributed in the fluid of the body.
2. Clearance can be computed reliably.
3. It is used to compute other parameters such as dose.
4. It is pharmacokinetic parameter including drug disposition, drug
elimination and drug excretion.
5. The values of clearance measured based on plasma clearance could be
interpreted physiologically.
PHYSIOLOGICAL INTERPRETATION OF THE DRUG CLEARANCE VALUES
• The systemic clearance may predominantly represent hepatic clearance.
For drugs undergoing extensive biotransformation, systemic clearance
mainly reflects the capacity of liver to metabolize these drugs.
• The clearance exceeding hepatic blood flow indicates the drug is
simultaneously metabolized by liver and extra hepatic site (renal/lungs).
For example: anesthetic propofol is cleared of blood through hepatic
lungs.
• For drugs solely eliminated by glomerular filtration the clearance
expected to reflect the GFR.
• Lower clearance relative to GFR represent renal clearance with drug re
absorption. For example: gentamicin.
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COMPETING TERMINOLOGIES
• Metabolism and excretion are the competing terminologies of clearance.
EXCRETION
• Excretion is the removal of drug from the body. The unit of excretion are
amount per unit of time. For example: mg/min.
• In excretion the drug may be inactivated but it no longer remains in your
body.
METABOLISM
• Metabolism activates prodrug or inactivates a drug which may remain in
the body.
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GM Hamad
B
Concentration
AUC
LINEAR AND NON-LINEAR
PHARMACOKINETICS
LINEAR PHARMACOKINETICS
• The linear pharmacokinetics is characterized by 1st
order kinetics in
distribution and elimination kinetics of a drug. The same order of
kinetics is assumed after increase of dose. For example, when the dose
of a drug is doubled, the concentration in blood is doubled.
• Graphically, linear pharmacokinetics can be demonstrated as given in
Figure 1.
• Majority of the drugs follows the linear pharmacokinetics.
NON-LINEAR PHARMACOKINETICS
• Being nonlinear means the effect of increase in one parameter results in
disproportional increase, decrease or no change in the other parameter.
In pharmacokinetics, the area under the curve (AUC), an absorption
parameter when plotted against three graded doses (increased
amounts) of drug it may proportionally increase, decrease or remains
unchanged.
• When the levels of AUC decrease or demonstrates no change with
increase in dose is called as the non-linear pharmacokinetics.
• Nonlinear pharmacokinetics is the deviations from the linear
pharmacokinetic profile of a drug.
A
Figure 1: Linear Pharmacokinetics, A) Concentration increased linearly with increase in
dose and B) Linear correlation between dose and area under the curve (AUC).
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GM Hamad
• A few drugs follows the nonlinear pharmacokinetics where an increase
in dose causes a nonlinear or disproportional change in blood
concentration and thus, area under the curve (AUC).
• Non-linearity leads to a higher or lower than the expected rise in
concentration or AUC with increased dose, as a result of dose-
dependent changes in absorption, distribution and elimination process.
Thus, the nonlinear kinetics is also known as capacity-saturation or
saturation kinetics.
• In non-linear pharmacokinetics, the kinetics of a process dealing with
drug deviates from the first order kinetics, which is the most commonly
followed in pharmacokinetic processes. In terms of kinetics, this
deviation is called as saturation kinetics, Michaelis-Menten of capacity-
limited kinetics.
CAUSES OF NON-LINEARITY
1. Saturation of process
2. Saturation of transporter
3. Saturation of enzyme
4. Pathologic conditions
5. Drug-induced
6. Disproportional activation of endogenous entities, e.g., ATPase, P-pg
PROCESSES INVOLVED IN NON-LINEAR PHARMACOKINETICS
• Nonlinear absorption results from saturation of carrier-mediated
transport causing lower than expected drug concentration with increase
in dose. In absorption, the saturation of pre systemic metabolism in gut
wall results in higher than the expected concentration since greater
proportion of administered dose survives the hepatic metabolism. For
instance, higher doses of salicylates saturate its glycine conjugation in
children.
• There are three categories of drugs which affect P-gp differently.
- Category I drugs can stimulate P-gp in low concentrations while
inhibit P-gp at higher concentrations.
- Category II drugs can produce dose dependent activation of
ATPase.
- Category III can inhibit activity of ATPase.
• The category I can lead to non-liner absorption/excretion/secretion due
to the distribution of P-gp at relevant locations.
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GM Hamad
BA
• Saturation of plasma protein binding causes nonlinear distribution and
occurs when the drug concentration exceeds binding capacity of protein,
an effect is pronounced with the basic drugs that bind to alpha-1 acid
glycoprotein due to lower concentration of this protein than that of the
albumin. However, nonsteroidal anti-inflammatory drugs and valproic
acid show nonlinear protein binding with albumin.
• Drugs saturating absorption or distribution are few and have no
significant effect on clinical dosing.
• Saturation of first pass metabolism in liver, respectively results in higher
than the expected concentration since greater proportion of
administered dose survives metabolism. For instance, higher doses of
salicylates saturate its glycine conjugation in children.
• Nonlinear elimination occurs with saturation of renal or biliary secretion.
Nonlinear elimination occurs for drugs undergoing hepatic metabolism
and taken at higher but within the clinical doses.
• Incremental dose of penicillin causes saturation of a transporter in renal
secretion of the drug leading to its non-linear elimination.
• Phenytoin saturates metabolism at upper range of clinical dose while
ethanol saturate even at lower dose.
INDICATION OF NON-LINEAR PHARMACOKINETICS
• In nonlinear elimination, rather than an exponential (first order) decline
in the plasma concentration, zero order elimination occurs initially
shown by a straight line on the linear plot and convex curve on
semilogarithmic graph.
• Until the concentration of drug falls sufficiently low, the elimination
returns to first order decline because the elimination process will no
longer be saturated (Figure 3).
Figure 3: Michaelis-Menten kinetics
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GM Hamad
A B
COMPARISON OF MICHAELIS-MENTEN KINETICS TO OTHER KINETICS ORDERS
• The order of kinetics is determined by the graphical method and each
order of kinetics gives a specific profile when drawn as concentration
against time and Ln-concentration against time (or on semilogarithmic
graph paper).
• With linear concentration, the first order is a curved line (Figure 4 A),
zero order kinetics shows a straight line (Figure 4 C) and the Michaelis-
Menten kinetic reflects a rapid decline and then a slow decline due to
saturation of the process (Figure 3 A).
• When the Ln-transformed concentration data is plotted on ordinary
graph (or the semilogarithmic graph is used), the first order becomes a
straight line (Figure 4 B) and zero order gives an upward curve in Figure
4 C.
• For the Michaelis-Menten kinetics, the line with Ln-transformed
concentration yields a slow and then a fast decline (Figure 1 B). The
profile in graph Figure 3 B deviates from linearity (zero order) and then
becomes linear (first order).
INTERPRETATION
• In first order kinetics the rate of decline of drug concentration depends
on the concentration. In zero-order kinetics, the decline is independent
of the drug concentration in the tissue.
• Michaelis Menten kinetics is usually applicable to drug elimination
where the drug elimination depends on the degree of saturation of the
elimination process. In this kinetics, the enzyme involved in drug
biotransformation is activated in a manner dependent on the drug
concentration.
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GM Hamad
C D
Equation 1
Equation 2 Equation 3
IMPACT OF NON-LINEARITY ON PHARMACOKINETICS
• Due to this complex kinetics, the equations used for linear
pharmacokinetics are not applicable, though the concept of
compartment model is still applicable.
• Application of linear pharmacokinetic models to drug showing nonlinear
pharmacokinetics may lead to large or frequent dosing leading to an
unexpected accumulation of drug.
• Nonlinear pharmacokinetic models require the application of more
complicated, enzyme or saturation (Michaelis-Menten) kinetic theory,
thus non-linear kinetics is also called as Michaelis-Menten kinetics.
PARAMETERS OF NON-LINEAR PHARMACOKINETICS
• It is clinically important to know the dose causing saturation of process
to avoid drug accumulation and toxicity.
• Knowledge of the maximal rate of elimination (Vmax) is important. The Km
is the concentration at the half maximal rate of elimination.
• The rate constant of decline, Vmax is calculated using equation for slope
(m) from the top left straight line on the linear graph. by using the
equation 1:
Vmax = −m
• The C0 (y-intercept) is estimated from the straight line at the top left of
the semilogarithmic graph.
• The Kel is calculated from the linear terminal slope of the curve on
semilogarithmic graph.
• The half-life is calculated as: 0.693/Kel.
• The Km and Vd are calculated using the equations 2 and 3:
km =
Vmax
kel
Vd =
Dose
C0
Figure 4: First order kinetics (A-B), and Zero order kinetics (C-D)
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APPLICATIONS OF PHARMACOKINETICS IN
CLINICAL SITUATIONS
Following are the areas where pharmacokinetic are applied:
• Individualization of drug dosing regimen
- Individual variations in particular patients.
• Therapeutic drug monitoring
- Involves monitoring of drug conc. in plasma for optimal drug
therapy.
• Therapeutic window
- Drugs having 2-3 therapeutic window, these drugs have narrow
therapeutic window
TW =
Max effective conc.
Minimum effective conc.
=
20 µg/ml
8 µg/ml
= 2.5µg/ml
• Candidates of therapeutic drug monitoring
• Availability of an assay procedure.
FACTORS INFLUENCING DRUG VARIABILITY
• Variation in drug absorption
• Presence of other drugs
• Drug interactions
• Genetic differences
• Physiological differences
• Pathophysiological condition of different people e.g. Immuno-
compromised patients.
DOSE INDIVIDUALIZATION
• Dose individualization is the determination of a sufficient dose which
delivers a safe drug.
• Concentration that is not toxic not below the minimum effective
concentration.
• Dose individualization is required for the drugs:
- With narrow therapeutic index
- Which follow non-linear pharmacokinetics
- With saturable in any pharmacokinetic process (e.g. metabolism)
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GM Hamad
- Where a relationship exists between blood concentration and
desired clinical effect
- Where a relationship exist between blood concentration and
adverse effects.
• Steps to dose individualization are as follows:
- Dose adjustment
- Pharmacokinetic studies
- Empirical dose to patients
THERAPEUTIC DRUG MONITORING
• TDM is individualization of dose to maintain blood drug concentration
within a target therapeutic window. TDM is the measurement of drug
concentration with the aim to adjust a dose to deliver concentration
within safety window. It is also called therapeutic concentration
monitoring.
• Pharmacokinetic is an important component of TDM. TDM is required
for category of drugs under dose individualization.
PROCESS OF THERAPEUTIC DRUG MONITORING
I. DEVELOPMENT OF PLASMA PROFILE IN EACH PATIENT
• Administering a pre-determined dose of drug based on:
- Manufacturer’s recommendation
- Patient’s condition
- Presence of other condition / disease state
- Previous experience of professional with the drug.
• Collection of blood samples
• Determination of drug conc. in each sample
• Plasma profile and pharmacokinetic model development.
II. OBSERVATION OF CLINICAL EFFECTS OF DRUGS IN PATIENTS
• Incorrect assay methodology
• Problem with patient compliance
III. DEVELOPMENT OF DOSAGE REGIMEN
Following are the methods to design dosage regimen:
• EMPERICAL DOSAGE REGIMEN
- It is designed by physician based on empirical clinical data,
personal experience and clinical observation.
• INDIVIDUAL DOSAGE REGIMEN
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GM Hamad
- It is based on the pharmacokinetics of drugs in the individual
patient.
- Suitable for hospitalized patients.
• DOSAGE REGIMEN BASED ON POPULATION AVERAGES
- It is based on one of two models
▪ FIXED MODEL
• Population average pharmacokinetic parameters are
used directly to calculate dosage regimens.
▪ ADAPTIVE MODEL
• Based on both population average pharmacokinetic
parameters of the drug as well as patient variable
such as weight.
DOSE ADJUSTMENT IN INFANTS & CHILDREN
• In children pharmacokinetics and pharmacodynamics of most of the
drugs are unknown. There is varied body composition in different age
groups. Different age groups require different doses.
• There is different liver maturity – conjugative enzymes are absent.
• According to FDA guidelines for industry 2000:
Parameter Age
Newborn infant Birth to 28 days
Infant 28 days to 23 months
Young child 2 to 5 years
Older child 6 to 11 years
Adolescent 12 to 18 years
Adult Above 18 years
• Infants have five immature pharmacokinetics:
1. Drug absorption
2. Renal excretion
3. Hepatic metabolism
4. Protein binding of drugs
5. Blood brain barrier
• Kidney function is 30 – 50% lesser than adult based on activity per unit
body weight. Reduced protein binding with albumin. Doses are required
to be adjusted based on half-life by taking into consideration of age and
body surface area.
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GM Hamad
DOSE ADJUSTMENT IN ELDERY PATIENTS
In elderly or Geriatrics (age >65) patients there is:
CHANGES IN DRUG ABSORPTION
• Decline in splanchnic blood
flow
• Altered GI motility
• Increase in gastric pH
• Alteration in gastrointestinal
absorptive surfaces
CHANGES IN DRUG DISTRIBUTION
• Decrease albumin
• Decrease protein binding
• Decreased body fat
• Decreased volume of
distribution
• Decreased muscle mass
CHANGES IN METABOLISIM AND EXCRETION
• Decreased glomerular filtration
• Decreased renal plasma flow
• Decreased cardiac output
• Decreased breathing capacity.
All of the above changes leads to age dependent verified drug concentration
which may lead to therapeutic failure or adverse effect or toxicity.
DOSE ADJUSTMENT IN OBESE PATIENTS
• In obesity, following are the changes:
- Body weight exceeds ideal body weight by 20%
- Body mass index (BMI) > 30 – 39.9
- Greater accumulation of fat tissues compared to muscle tissue
causing lower proportion of total body water.
• These leads to changes in Vd – Vd is increased.
• Altered pharmacokinetic due to distributional changes because of drug
partitioning of drug from aqueous to fat environment. Also, changes in
the liver and cardiovascular conditions. Thus, accumulation occurs at
normal dose.
BMI = [
Weight (lb)
Height (inch)2
] X 703
BMI = [
Weight (kg)
Height (cm)2
] X 10,000
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LEAN BODY WEIGHT
LBW (males) = 50kg + 2.3kg for each inch over 5ft.
LBW (females) = 45.5kg + 2.3kg for each inch over 5ft.
Terms BMI Values
Underweight < 18.5
Normal 18.5 – 24.9
Overweight 25 – 29.9
Obese 30 – 39.9
Extreme obesity > 40
DOSE ADJUSTMENT IN PREGNANCY
• Little information is available in literature.
• Plasma concentration of certain drugs may reduce during pregnancy.
• Example: phenytoin and phenobarbitone.
DOSE ADJUSTMENT IN DISEASE STATES
• Diseases alter the drug concentrations due to change in pharmacokinetic
processes.
- In renal disease, drug clearance is reduced and the half-life is
prolonged.
- Liver diseases impairs clearance of drugs which depends upon
bioconversion to more water-soluble compounds.
- CHF can cause elevated drug levels for drug dependent on hepatic
metabolism for clearance.
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BIOAVAILABILITY AND BIOEQUIVALENCE
INTRODUCTION
• Bioavailability is the total amount of an intact drug available
systematically after administration of the drug. It is the relative amount
of an administered drug reaching to general circulation and the rate at
which it occurs.
PURPOSE OF BIOAVAILABILITY STUDIES
• Bioavailability studies are performed for both approved active drug
ingredients and therapeutic moieties not yet approved for marketing by
the FDA.
• New formulations of active drug ingredients must be approved by the
FDA before marketing.
• In approving a drug product for marketing, the FDA ensures that the
drug product is safe and effective for its labeled indications for use.
• Moreover, the drug product must meet all applicable standards of
identity, strength, quality, and purity.
• To ensure that these standards are met, the FDA requires bioavailability
/pharmacokinetic studies and, where necessary, bioequivalence studies
for all drug products.
• Bioavailability may be considered as one aspect of drug product quality
that links in-vivo performance of the drug product used in clinical trials
to studies demonstrating evidence of safety and efficacy.
• For un-marketed drugs that do not have full NDA approval by the FDA,
in-vitro and/or in-vivo bioequivalence studies must be performed on the
drug formulation proposed for marketing as a generic drug product.
• Furthermore, the essential pharmacokinetics of the active drug
ingredient or therapeutic moiety must be characterized.
• Essential pharmacokinetic parameters, including the rate and extent of
systemic absorption, elimination half-life, and rates of excretion and
metabolism, should be established after single- and multiple-dose
administration.
• Data from these in-vivo bioavailability studies are important to establish
recommended dosage regimens and to support drug labeling.
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GM Hamad
• In-vivo bioavailability studies are also performed for new formulations of
active drug ingredients or therapeutic moieties that have full NDA
approval and are approved for marketing.
• The purpose of these studies is to determine the bioavailability and to
characterize the pharmacokinetics of the new formulation, new dosage
form, or new salt or ester relative to a reference formulation.
• Clinical studies are useful in determining the safety and efficacy of drug
products.
• Bioavailability studies are used to define the effect of changes in the
physicochemical properties of the drug substance and the effect of the
drug product (dosage form) on the pharmacokinetics of the drug.
• Bioequivalence studies are used to compare the bioavailability of the
same drug (same salt or ester) from various drug products.
• Bioavailability and bioequivalence can also be considered as
performance measures of the drug product in-vivo.
• If the drug products are bioequivalent and therapeutically equivalent,
then the clinical efficacy and the safety profile of these drug products
are assumed to be similar and may be substituted for each other.
TYPES OF BIOAVAILABILIY
1. RELATIVE BIOAVAILABILITY
• Relative (apparent) bioavailability is the extent of absorption (as
measured by AUC) of a drug as compared to a recognized standard or
reference product, both of which given through oral or other route but
not through I/V route. A drug the availability of which is compared is
called the test formulation. The reference or standard drug is usually
with known extent of bioavailability. The relative bioavailability of a drug
can be estimated by blood data or by the urine data.
• Sometimes the relative bioavailability can be used to compare different
conditions as well such as fasting, exercise, etc.
RELATIVE BIOAVAILABILITY BY BLOOD DATA
• In blood data, relative bioavailability is calculated by the comparing AUC
of test and reference drugs. When the test and the reference drug
products given at the same dosage level, the relative bioavailability can
be obtained for the formula:
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GM Hamad
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐴𝑈𝐶] 𝑇𝑒𝑠𝑡
[𝐴𝑈𝐶] 𝑅𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒
• If the above equation is multiplied by 100, it will give percent availability.
• When different doses are administered, a correction for the size of the
dose is made as given in the formula:
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐴𝑈𝐶] 𝑇𝑒𝑠𝑡 / 𝐷𝑜𝑠𝑒 𝑇𝑒𝑠𝑡
[𝐴𝑈𝐶] 𝑅𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 / 𝐷𝑜𝑠𝑒 𝑅𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒
RELATIVE BIOAVAILABILITY BY URINE DATA
• Urinary drug excretion data may also be used to measure relative
availability whereby the total amount of drug excreted in urine (𝐷 𝑢
∞
) after
administration of test (T) and reference (R) drugs by using the following
formula:
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐷 𝑢
∞] 𝑇
[𝐷 𝑢
∞] 𝑅
• The percent relative availability using urinary excretion data can be
obtained by multiplying the above equation with 100.
2. ABSOLUTE AVAILABILITY
• Absolute bioavailability is the extent of absorption of a drug after
extravascular administration (e.g., oral, rectal, transdermal,
subcutaneous) as compared to the extent of the drug availability after
administered through I/V route. Thus, absolute bioavailability of drug is
measured by comparing the respective AUCs after extravascular and IV
administration of a drug.
• The absolute bioavailability of a drug using plasma data/ blood data can
be measured as follows:
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐴𝑈𝐶] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂
[𝐴𝑈𝐶]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉
• Absolute availability using urinary drug excretion data can be
determined by using the following formula:
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =
[𝐷 𝑢
∞] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂
[𝐷 𝑢
∞]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉
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GM Hamad
• The absolute bioavailability is also equal to fraction of the dose that is
bioavailable, abbreviated as F. When absolute availability is expressed in
percent, then F = 1 or 100%.
• For drugs given intravascularly or the one which is chemically stable in
gastrointestinal tract, such as by IV bolus injection, F = 1 because all of
the drug is completely absorbed.
• For a drug given through extravascular route or the drugs which undergo
first pass effect, the F is always ≤ 1.
METHODS FOR ASSESSING BIOAVAILABILITY
• Assessment of bioavailability is the estimation of the absorption of drug
after its administration.
• Methods of bioavailability assessment depends on the assumption that
the measurement of the concentration of the drug in a suitable body
fluid (usually blood, plasma, urine or occasionally saliva) over period of
time after administration can be correlated with the clinical efficacy the
drug in treating a given disease condition.
• Term bioavailability encompasses the extent of drug absorption and the
rate of drug absorption thus, the bioavailability of drug from a drug
demands the assessment of the extent and rate of drug absorption of
the drug.
SIGNIFICANCE OF MEASURING BIOAVAILABILITY
• Bioavailability assessment is required for the following situations:
- Characterization of the pharmacokinetics of new drug molecules
- All new drug formulation
- New dosage form of a drug
- New dosage strength or dosage regimen
- New salt or ester of a drug
- New indication of a drug
- Administration of drug in special population, e.g., pediatrics
- Change in manufacturing process
- To determine the safety and efficacy of the drug products
- A legal requirement from the drug authorities.
1. BIOAVAILABILITY ASSESSMENT BASED ON BLOOD DATA
• Blood data refers to concentration-time data obtained from blood,
plasma or serum after administration of drug. The parameters studied in
this method are peak plasma (or serum, blood) concentration (Cmax),
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GM Hamad
time to reach peak plasma concentration (tmax) and area under the
plasma level time curve (AUC).
PEAK PLASMA CONCENTRATION (Cmax)
• The peak plasma concentration, Cmax represents the maximum
concentration of drug in blood plasma following oral administration of a
drug. This is usually related to dose and rate constant for absorption and
elimination of the drug.
• Usually, a relationship exists between pharmacodynamic effect and the
plasma drug concentration.
• Cmax reflects that a drug is sufficiently absorbed systemically to provide a
therapeutic response.
• Cmax provides warning of possible toxic levels of drugs.
UNITS
• The Cmax is measured in terms of concentration, i.e., µg/ml, ng/ml, etc.
• Although not a unit for rate, Cmax is often used in bioequivalence studies
as a surrogate measure for the rate of drug bioavailability.
ESTIMATION OF Cmax
• Graphical method
- Cmax can be measure directly observing on the plasma level time
curve.
• Direct method
- Direct method for estimation of Cmax involves applying formula:
𝐶 𝑚𝑎𝑥 =
𝐹𝐷0 𝐾𝑎
𝑉𝑑(𝐾𝑎 − 𝐾)
(𝑒−𝐾𝑡 𝑚𝑎𝑥 − 𝑒−𝐾𝑎𝑡 𝑚𝑎𝑥)
- Where, F = fraction of dose absorbed, D0 = dose of drug, ka =
absorption rate constant, k = overall rate constant and tmax is the
time for peak plasma concentration.
TIME FOR MAXIMUM CONCENTRATION (Tmax)
• Time to reach maximum concentration (Cmax), tmax is time required to
reach maximum drug concentration after drug administration. At this
point, the absorption is maximum, and the rate of drug absorption
equals the rate of drug elimination. However, drug absorption continues
but at a slower rate after this point.
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• The tmax is a measure of the rate of drug absorption. A lower tmax value
represents a faster absorption of drug. Usually, two drugs with same
rate (tmax) and extent of absorption (AUC, Cmax), are considered
equivalent.
• In some special cases, where rate of absorption is different, but the
extent is same, the products are considered equivalent.
UNITS OF Tmax
• The tmax is represented in the units of time, i.e., hours, or minutes.
ESTIMATION OF Tmax
• Graphical method
- Time to reach peak plasma concentration is estimated by direct
reading from the plasma concentration versus time profile.
• Direct method
- Direct method for estimation of Tmax involves applying formula:
𝑡max =
2.303
𝐾𝑎 − 𝐾
log
𝐾𝑎
𝐾
- Where ka is the absorption rate constant, k is the overall rate
constant.
AREA UNDER THE CURVE (AUC)
• Area under the curve (AUC0-∞) is the area under the drug plasma level-
time curve from t = 0 to t = ∞ and reflects the total amount of active
drug which reaches the systemic circulation following administration of
drug.
• The drug plasma level-time curve provides the quantitative
measurement for bioavailability. The exact shape of plasma
concentration profile depends on the relative rates of absorption and
elimination and routes of drug administration. Intravenous and
sometimes, intramuscular routes yields an early peak due to the fast or
almost instantaneous absorption. Whereas oral, subcutaneous, rectal,
and other routes demonstrate delayed peaks due to comparatively
slower rates of absorption.
• The AUC is independent of the route of administration and processes of
drug elimination provided the elimination processes do not change. For
many drugs, AUC is directly proportion to their dose. In some cases, the
55
GM Hamad
AUC is not directly proportional to the administered dose for all dosage
levels. This is due to the reason that one of the pathways for drug
elimination may become saturated. In such case, the AUC increases
disproportionally to the increase in dose. The drug pharmacokinetic
profile is said to be dose dependent. For the drugs having the dose-
dependent kinetics, the bioavailability assessment is difficult.
• AUC reflects the following phases:
- Absorption phase in which the absorption is greater than
elimination.
- Distribution phase which is characterized by absorption ≈
elimination.
- Elimination phase in which initially absorption rate < elimination
rate, then absorption = 0 and at the end, elimination = 0.
UNITS OF AUC
• AUC is measured in terms of concentration × time, thus, its units are
µg.hr/ml, ng.hr/ml or mg.hr/l
CALCULATION OF AUC0-∞
• Trapezoidal Rule
- Trapezoidal rule involves the breaking up of the plasma
concentration vs time profile into various trapezoids (small
segments).
- Calculating the areas of the individual trapezoids and then added
up these areas gives the AUC.
𝐴𝑈𝐶0−𝑡𝑛 =
𝐶 𝑛−1 + 𝐶1
2
(𝑡 𝑛 − 𝑡 𝑛−1)
- Where Cn = Concentration of drug under consideration, Cn-1 =
concentration of drug in plasma prior to that concentration which
is under consideration. While tn and tn-1 are the time of absorption
corresponding to Cn and Cn-1, respectively.
• Direct method
- Under direct method for calculation of AUC0- is use of certain
formulae which are as follows:
[𝐴𝑈𝐶]0
∞
= ∫ 𝐶𝑝𝑑𝑡
∞
0
56
GM Hamad
[𝐴𝑈𝐶]0
∞
=
𝐹𝐷0
𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒
=
𝐹𝐷0
𝐾𝑉𝑑
- Where F = dose absorbed; D0 = dose; k = elimination rate
constant; and Vd is the volume of distribution.
2. BIOAVAILABILITY ASSESSMENT BASED ON URINE DATA
• Urinary drug excretion data is an indirect method for estimation of the
bioavailability.
• Bioavailability assessment by urinary data is based upon the assumption
that the appearance of drug or its metabolite(s) in urine is the function
of the rate and extent of absorption. This assumption, however, is valid
only when:
- Drug and/or its metabolites is extensively excreted in urine.
- Rate of urinary excretion is proportional to the concentration of
intact drug in blood plasma. This proportionality does not hold if:
▪ The drug and/or its metabolites is excreted by an active
transport process into distal kidney tubules.
▪ The intact drug and/or metabolites is weakly acidic or
weakly basic (i.e., there rate of excretion depends upon
urinary pH.
▪ The excretion rate depends on rate of urine flow.
TOTAL AMOUNT OF DRUG EXCRETED THROUGH URINE (𝑫 𝒖
∞
)
• Total amount of drug excreted through urine (𝐷 𝑢
∞
) is also referred to as
the drug ultimately excreted and abbreviated as
𝐴 𝑢
∞
. The cumulative amount of drug excreted in
the urine is proportional to the total amount of
drug absorbed. A drug absorbed more; more
drug appears in urine.
• A cumulative urinary excretion curve is obtained
by collecting urine samples at known intervals
of time following administration. Enough time is
required to collect the entire absorbed drug in
urine, which is 5 × t½.
• A cumulative urinary excretion curve and the corresponding
plasma concentration-time curve obtained after the
administration of a single dose of a drug by oral route is given in Figure
1-2.
Figure 1
57
GM Hamad
• This figure reflects the corresponding plasma
level time plot and the cumulative urinary
drug excretion. The initial A-B reflects the
absorption and the slope of this segment of
urinary excretion curves is related to the rate
of absorption of the drug into blood.
• The total amount of intact drug is excreted in
urine at point C corresponds to the time at
which the plasma concentration of intact drug
is zero and essentially all the drug has been eliminated from
the body. At this point Du
∞
is obtained.
URINARY EXCRETION RATE (dDu/dt)
• The elimination follows the first order rate
process. The rate of drug excretion depends on
the first order elimination rate constant and the
drug concentration in plasma.
• The plots of plasma level vs time and the rate of
urinary excretion rate vs time are similar as
depicted in figure which indicates the
corresponding plots relating plasma level-time
curve and the rate of urinary drug excretion.
• The maximum rate of drug excretion would be at point B. While
minimum rate of excretion would be at points A and C.
TIME FOR COMPLETE EXCRETION (t∞
)
• In the Figure 3-4, the slope of the curve
segment AB is related to the rate of drug
absorption whereas point C is related to the
total time required after drug administration
for the drug to be absorbed and completely
excreted (t = ∞).
• The t∞
is a useful parameter in bioequivalence
studies comparing drug products.
Figure 2
Figure 3
Figure 4
Figure 4
58
GM Hamad
3. BIOAVAILABILITY ASSESSMENT BASED ON THE ACUTE
PHARMACODYNAMIC RESPONSE
• In some cases, the quantitative measurement of a drug in plasma or
urine lacks an assay with sufficient accuracy and/or reproducibility.
• For locally acting, non-systemically absorbed drug products, such as
topical corticosteroids, plasma drug concentrations may not reflect the
bioavailability of the drug at the site of action.
• An acute pharmacodynamic effect, such as an effect on forced
expiratory volume, FEV1 (inhaled bronchodilators) or skin blanching
(topical corticosteroids) can be used as an index of drug bioavailability.
• In this case, the acute pharmacodynamic effect is measured over a
period of time after administration of the drug product.
• Measurements of the pharmacodynamic effect should be made with
sufficient frequency to permit a reasonable estimate for a time period at
least three times the half-life of the drug.
• This approach may be particularly applicable to dosage forms that are
not intended to deliver the active moiety to the bloodstream for
systemic distribution.
• The use of an acute pharmacodynamic effect to determine
bioavailability generally requires demonstration of a dose–response
curve.
• Bioavailability is determined by characterization of the dose–response
curve.
• For bioequivalence determination, pharmacodynamic parameters
including the total area under the acute pharmacodynamic effect–time
curve, peak pharmacodynamic effect, and time for peak
pharmacodynamic effect are obtained from the pharmacodynamic
effect–time curve.
• The onset time and duration of the pharmacokinetic effect may also be
included in the analysis of the data.
• The use of pharmacodynamic endpoints for the determination of
bioavailability and bioequivalence is much more variable than the
measurement of plasma or urine drug concentrations.
4. BIOAVAILABILITY ASSESSMENT BASED ON RADIOMETRIC METHOD
• The radiometric method is based on the radioactivity measurement and
involves the administration of radiolabeled drug moiety and determining
the total radioactivity in plasma or urine.
59
GM Hamad
• The estimation of relative availability is based upon the area under the
concentration of total radioactivity, apparent drug (or metabolites) in
plasma versus time curve.
• Sometimes, the estimation under this method is based on the
cumulative urinary excretion of total radioactivity.
• The method can also reflect the localization of the drug sat several tissue
level and pattern of the drug distribution.
5. BIOAVAILABILITY ASSESSMENT BASED ON CLINICAL OBSERVATION
• Well-controlled clinical trials in humans establish the safety and
effectiveness of drug products and may be used to determine
bioavailability.
• It is the least accurate, least sensitive, and least reproducible approach
• The FDA considers this approach only when analytical methods and
pharmacodynamic methods are not available.
• Comparative clinical studies have been used to establish bioequivalence
for topical antifungal drug products (e.g. ketoconazole) and for topical
acne preparations.
• For dosage forms intended to deliver the active moiety to the
bloodstream for systemic distribution, this approach may be considered
acceptable only when analytical methods cannot be developed to permit
use of one of the other approaches.
6. BIOAVAILABILITY ASSESSMENT BASED ON IN-VITRO STUDIES
• Drug dissolution studies may under certain conditions give an indication
of drug bioavailability.
• Ideally, the in-vitro drug dissolution rate should correlate with in-vivo
drug bioavailability.
• Dissolution studies are often performed on several test formulations of
the same drug.
• The test formulation that demonstrates the most rapid rate of drug
dissolution in vitro will generally have the most rapid rate of drug
bioavailability in vivo.
BIOEQUIVALENCE STUDIES
• Difference in preclinical response or adverse event may be due to:
- Difference in PK and/or PD behavior of drug.
- Difference in bioavailability of drug from drug product.
60
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Biopharmaceutics complete notes

  • 1. BIOPHARMACEUTICS & PHARMACOKINETICS 4th PROFESSIONAL GHULAM MURTAZA HAMAD 4th PROFF. EVENING PUNJAB UNIVERSITY COLLEGE OF PHARMACY, LAHORE Reference Dr. Nadeem Irfan Bukhari Lectures Shargel – Applied Biopharmaceutics and Pharmacokinetics, 7th edition MADAN PL – Biopharmaceutics and Pharmacokinetics, 2nd edition Gilbert S Banker – Modern Pharmaceutics, 4th edition
  • 2. GM Hamad TABLE OF CONTENTS Contents 1. Definitions and Terminology 2. Gastrointestinal Absorption 3. Biological Half Life and Volume of Distribution 4. Drug Clearance 5. Linear and Non-linear Pharmacokinetics 6. Bioavailability and Bioequivalence 7. Concept of Compartment Models 8. Multiple Dosage Regimen 9. Elimination of Drugs 10. Protein Binding 11. Pharmacokinetic Variations in Disease State 12. Intravenous Infusion 13. Biopharmaceutical Aspects in Developing a Dosage Form 14. In-Vitro-In-Vivo Correlation (IVIVC)
  • 3. GM Hamad DEFINITIONS AND TERMINOLOGY BIOPHARMACEUTICS • “Biopharmaceutics interrelates physicochemical properties of drug, characteristics of dosage form, and site (route) of administration to the rate and extent of systemic drug absorption” • Biopharmaceutics encompasses factors that influence: 1. Stability of drug within drug product 2. Release of drug from drug product 3. Rate of dissolution/release of drug at the absorption site 4. Systemic absorption of drug. SCHEME DEMONSTRATING THE DYNAMIC RELATIONSHIP BETWEEN THE DRUG, THE DRUG PRODUCT, AND THE PHARMACOLOGIC EFFECT • Efficacy (in-vivo performance) and safety of drug product critically depends on: - Physicochemical characteristics of active pharmaceutical ingredient (API/drug substance) - Characteristics of dosage form. - Features of the route of administration. • Sequence of events to elicit a therapeutic effect: (LADMER) - Administration (either by an oral, intravenous, subcutaneous, transdermal, etc. route) - Liberation (release) of drug from dosage form in a predictable and characterizable manner. - Absorption (into the blood) - Distribution (+ to the site of action) 1
  • 4. GM Hamad - Metabolism - Excretion - Response (Therapeutic effect) • Studies in biopharmaceutics use both in vitro and in vivo methods. - In vitro methods are procedures employing test apparatus and equipment without involving laboratory animals or humans. - In vivo methods are more complex studies involving human subjects or laboratory animals. PHARMACOKINETICS • Pharmacokinetics is the science of the kinetics of drug absorption, distribution, and elimination (i.e. metabolism and excretion) • The description of drug distribution and elimination is termed drug disposition. • The study of pharmacokinetics involves both experimental and theoretical approaches. • The experimental aspect of pharmacokinetics involves the development of biologic sampling techniques, analytical methods for the measurement of drugs and metabolites, and procedures that facilitate data collection and manipulation. • The theoretical aspect of pharmacokinetics involves the development of pharmacokinetic models that predict drug disposition after drug administration. • The application of statistics is an integral part of pharmacokinetic studies. Statistical methods are used for pharmacokinetic parameter estimation and data interpretation ultimately for the purpose of designing and predicting optimal dosing regimens for individuals or groups of patients. Statistical methods are applied to pharmacokinetic models to determine data error and structural model deviations. CLASSICAL PHARMACOKINETICS • A study of theoretical models focusing mostly on model development and parameterization. POPULATION PHARMACOKINETICS • A study of pharmacokinetic differences of drugs in various population groups. 2
  • 5. GM Hamad CLINICAL PHARMACOKINETICS • A multidisciplinary approach to individually optimized dosing strategies for a specific patient based on the patient's disease state and patient- specific considerations. • Clinical Pharmacokinetics involves in optimum dosing regimens to produce desired pharmacologic response in majority of anticipated patient population. - Largely dependent on intra- and inter-individual variations which results in in either a subtherapeutic or toxic response thus, may requiring adjustment of the dosing regimen. • Clinical pharmacokinetics is the application of pharmacokinetic methods to drug therapy. PHARMACODYNAMICS • Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body; this includes the mechanisms of drug action and the relationship between drug concentration and effect. RELATIONSHIP OF BIOPHARMACEUTICS WITH PHARMACOKINETICS AND PHARMACODYNAMICS • Drug action depends upon biopharmaceutics and pharmacokinetics. It interrelates the blood drug concentration to: - Sub-therapeutic (drug concentration below the MEC) - Toxic response (drug concentration above the MEC) - Onset of drug action - Duration of drug action DRUG ALTERNATIVES • Alternatives - (of one or more things) available as another possibility or choice. 1. PHARMACEUTICAL ALTERNATIVES • Pharmaceutical alternatives - Drug products that contain same APIs but as different salts/ esters/ complex or forms. - Tetracycline phosphate or tetracycline HCl equivalent to 250 mg tetracycline base. - Different dosage forms and strengths within a product line by a single manufacturer. 3
  • 6. GM Hamad - Examples i. Extended-release and immediate release dosage forms of same APIs. ii. Tablet and Capsule containing the same API in the same dosage strength. 2. THERAPEUTIC ALTERNATIVES • Therapeutic alternatives - products containing different API that are indicated for the same therapeutic or clinical objectives. - From same pharmacologic class and are expected to have the same therapeutic effect. - E.g., ibuprofen and aspirin DRUG EQUIVALENTS • Equivalents - equal in value, amount, function, meaning, etc. 1. PHARMACEUTICAL EQUIVALENTS • Pharmaceutical (Chemical) equivalents are the products: - Having same APIs (same salt or ester) - Having same strength, quality and purity - Used through the same route - They are also therapeutic equivalents - They may differ in characteristics such as shape, color, flavor, scoring configuration, release mechanisms, packaging, excipients, expiration time, and, within certain limits, labeling. 2. THERAPEUTICAL EQUIVALENTS • Therapeutic equivalents – Products which are: - Pharmaceutical equivalents (same APIs, amount of APIs, dosage forms, routes) - Generic equivalent (having same APIs as the same salt in same dosage form (but made by a different manufacturer). - Same bioavailability (Bioequivalent) - Expected to have same clinical effect and safety profile when administered under the conditions specified in the labeling. DRUG SUBSTITUTION • Substitution – act of providing a thing in place of another (always giving an alternative) 4
  • 7. GM Hamad 1. PHARMACEUTICAL SUBSTITUTION • Pharmaceutical substitution - Dispensing a pharmaceutical alternative for a prescribed drug product. - E.g. Dispensing of ampicillin suspension in place of ampicillin capsules. - E.g. Tetracycline HCl in place of tetracycline phosphate. - Generally, requires the physician's approval. 2. THERAPEUTIC SUBSTITUTION • Therapeutic substitution - Dispensing a therapeutic alternative in place of the prescribed drug product. - For example, ibuprofen instead of naproxen. 3. GENERIC SUBSTITUTION • Generic substitution - dispensing a different brand or an unbranded drug product in place of the prescribed drug product. - Substituted drug product must be Pharmaceutical equivalents (having same API as same salt in same dosage form but is made by a different manufacturer. - E.g. Substitution of Motrin brand of ibuprofen in place of Advil brand of ibuprofen if permitted by physician. GENERIC EQUIVALENCE • These are the same API’s in same salts, same chemical form and dosage forms, ideally bioequivalent pharmaceutical content. BIOEQUIVALENCE • Relationship in terms of bioavailability, therapeutic response, or a set of established standards of one drug product to another. BIOEQUIVALENT DRUG PRODUCTS • This term describes pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions. BIOAVAILABILITY • Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be 5
  • 8. GM Hamad absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. ABSOLUTE BIOAVAILABILITY • The absolute bioavailability of drug is the systemic availability of a drug after extravascular administration compared to IV dosing. • The absolute bioavailability of a drug is generally measured by comparing the respective AUCs after extravascular and IV administration. • Absolute bioavailability after oral drug administration using plasma data can be determined as follows: 𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐴𝑈𝐶] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂 [𝐴𝑈𝐶]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉 • Absolute availability using urinary drug excretion data can be determined by the following: 𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐷 𝑢 ∞] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂 [𝐷 𝑢 ∞]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉 RELATIVE BIOAVAILABILITY • Relative (apparent) bioavailability is the bioavailability of the drug from a drug product as compared to a recognized standard. • The availability of drug in the formulation is compared to the availability of drug in a standard dosage formulation, usually a solution of the pure drug evaluated in a crossover study. • The relative bioavailability of two drug products given at the same dosage level and by the same route of administration can be obtained using the following equation: 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐴𝑈𝐶] 𝐴 [𝐴𝑈𝐶] 𝐵 - where drug product B is the recognized reference standard. This fraction may be multiplied by 100 to give percent relative bioavailability. • When different doses are administered, a correction for the size of the dose is made, as in the following equation: 6
  • 9. GM Hamad 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐴𝑈𝐶] 𝐴 / 𝐷𝑜𝑠𝑒 𝐴 [𝐴𝑈𝐶] 𝐵 / 𝐷𝑜𝑠𝑒 𝐵 • Urinary drug excretion data may also be used to measure relative availability, as long as the total amount of intact drug excreted in the urine is collected. The percent relative availability using urinary excretion data can be determined as follows: 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐷 𝑢 ∞] 𝐴 [𝐷 𝑢 ∞] 𝐵 - where [Du]∞ is the total amount of drug excreted in the urine. DRUG ELIMINATION • Drug elimination refers to the irreversible removal of drug from the body by all routes of elimination. • Drug elimination is usually divided into two major components: - Excretion - Biotransformation EXCRETION • Drug excretion is the removal of the intact drug. • Nonvolatile and polar drugs are excreted mainly by renal excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the urine. • Other pathways for drug excretion may include the excretion of drug into bile, sweat, saliva, milk (via lactation), or other body fluids. • Volatile drugs, such as gaseous anesthetics, alcohol, or drugs with high volatility, are excreted via the lungs into expired air. BIOTRANSFORMATION • Biotransformation or drug metabolism is the process by which the drug is chemically converted in the body to a metabolite. • Biotransformation is usually an enzymatic process. A few drugs may also be changed chemically by a nonenzymatic process (e.g. ester hydrolysis). The enzymes involved in the biotransformation of drugs are located mainly in the liver. • Other tissues such as kidney, lung, small intestine, and skin also contain biotransformation enzymes. 7
  • 10. GM Hamad DRUG CLEARANCE • Drug clearance is defined as the fixed volume of fluid (containing the drug) removed from the drug per unit of time. The units for clearance are volume/time (e.g. mL/min, L/h). • Drug clearance is a pharmacokinetic term for describing drug elimination from the body without identifying the mechanism of the process. • Drug clearance (also called body clearance or total body clearance) considers the entire body as a single drug-eliminating system from which many unidentified elimination processes may occur. DRUG DISPOSITION • It refers to the fate of drug after absorption. On reaching bloodstream, drugs are simultaneously distributed throughout body and eliminated. • Distribution usually occurs much more rapidly than elimination. Rate of distribution to tissues of each organ is determined by blood flow perfusing organs and ease with which drug molecules cross capillary wall and penetrate cells of particular tissue. OTHER TERMINOLOGY REFERENCE LISTED DRUG (RLD) • Reference listed drug (RLD) - the drug product on which an applicant relies when seeking approval of an Abbreviated New Drug Application (ANDA). - RLD is generally the brand-name drug that has a full New Drug Application (NDA). - The FDA designates a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent. MULTISOURCE DRUG PRODUCT • Multisource drug product is a drug product that contains the same active drug substance in the same dosage form and is marketed by more than one pharmaceutical manufacturer. SINGLE SOURCE DRUG PRODUCT • Single source drug product is a drug product for which patent has not yet expired or has certain exclusivities so that only one manufacturer can make it. 8
  • 11. GM Hamad GASTROINTESTINAL ABSORPTION INTRODUCTION • It is defined as “the process of movement of unchanged drug from the site of administration to the systemic circulation. • There always present a correlation between plasma concentration of a drug and the therapeutic response thus, absorption can also be defined as the “process of movement of unchanged drug from the site of administration to the site of measurement. i.e. plasma”. STRUCTURE OF CELL MEMBRANE • Cell membrane separates living cell from nonliving surroundings. - Thin barrier = 8 nm thick • Controls traffic in and out of the cell - Selectively permeable: allows some substances to cross more easily. than others. - Hydrophobic vs hydrophilic • Made of phospholipids, proteins and other macromolecules. • Proteins determine membrane’s specific functions. - Cell membrane and organelle membranes each have unique collections of proteins. • Membrane proteins: - Peripheral proteins ▪ Loosely bound to surface of membrane. ▪ Cell surface identity marker (antigens) • Integral proteins: - Penetrate lipid bilayer, usually across whole membrane - Transmembrane protein transport proteins ▪ Channels, permeases (pumps) PHYSIOLOGICAL FACTORS AFFECTING ORAL ABSORPTION • Passage of drugs across membrane. 9
  • 12. GM Hamad 1. Passive diffusion 2. Pore transport 3. Active transport 4. Facilitated diffusion 5. Pinocytosis 6. Ion pair formation MECHANISMS OF DRUG ABSORPTION 1. PASSIVE DIFFUSION CHARACTERISTICS • Diffusion - Movement from high to low concentration. • Major process for absorption of more than 90% of drugs. • Non-ionic diffusion. • Driving force: Concentration or electrochemical gradient. • Difference in the drug concentration on either side of the membrane. • Drug movement is a result of kinetic energy of molecules. FICK’S FIRST LAW OF DIFFUSION • Expressed by Fick’s first law of diffusion: - “The drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained and the rate of diffusion is directly proportional to the concentration gradient across the membrane”. dQ dt = D A Km/w h (CGIT − CP) - Where, ▪ dQ/dt = rate of drug diffusion (amount/time) ▪ D = diffusion coefficient of the drug ▪ A= surface area of the absorbing membrane for drug diffusion ▪ Km/w = partition coefficient of drug between the lipoidal membrane and the aqueous GI fluids ▪ h = thickness of the membrane ▪ (CGIT – Cp) = difference in the concentration of drug in the GI fluids and the plasma (Concentration Gradient) - SINK CONDITION ▪ The passively absorbed drug enters blood, rapidly swept away and distributed into a larger volume of body fluids. 10
  • 13. GM Hamad ▪ Hence, the concentration of drug at absorption site CGIT is maintained greater than the concentration in the plasma. Such a condition is called as sink condition for drug absorption. ▪ Under usual absorption conditions, D, A, Km/w and h are constants, the term D A Km/w /h can be replaced by a combined constant P called as permeability coefficient. ▪ Permeability: Ease with which a drug can permeate or diffuse through a membrane. ▪ Due to sink conditions, the C is very small in comparison to CGIT. dQ dt = P CGIT 2. PORE TRANSPORT • Also known as convective transport, bulk flow or filtration. • Important in the absorption of low mol. Wt. (less than 100). Low molecular size (smaller than the diameter of the pore) and generally water-soluble drugs e.g. urea, water and sugars. • The driving force for the passage of the drugs is the hydrostatic or the osmotic pressure difference across the membrane. • Mechanism – through the protein channel present in the cell membrane. • Drug permeation through pore transport – renal excretion, removal of drug from CSF and entry of drug into the liver. • Rate of absorption via pore transport depends on the number and size of the pores, and given as follows: dc dt = N R2 A ∆C (η) (h) • where, - dc/ dt = rate of the absorption. - N = number of pores - R = radius of pores - ∆C = concentration gradient - η = viscosity of fluid in the pores - h = thickness of the membrane 11
  • 14. GM Hamad 3. ION-PAIR TRANSPORT • Responsible for absorption of compounds which ionizes at all pH values. e.g. quaternary ammonium, sulphonic acids. • Ionized moieties forms neutral complexes with endogenous ions which have both the required lipophilicity and aqueous solubility for passive diffusion. • E.g. Propranolol, a basic drug that forms an ion pair with oleic acid and is absorbed by this mechanism. 4. IONIC OR ELECTROCHEMICAL DIFFUSION • Charge on membrane influences the permeation of drugs. • Molecular forms of solutes are unaffected by the membrane charge and permeate faster than ionic forms. • The permeation of anions and cations is also influenced by pH. Once inside the membrane, the cations are attached to negatively charged intracellular membrane, thus giving rise to an electrical gradient. • If the same drug is moving from a higher to lower concentration, i.e. moving down the electrical gradient, the phenomenon is known as electrochemical diffusion. • Thus, at a given pH, the rate of permeation may be as follows: - Unionized molecule > anions > cations. 5. CARRIER MEDIATED TRANSPORT • Involves a carrier which reversibly binds to the solute molecules and forms a solute-carrier complex. • This molecule transverse across the membrane to the other side and dissociates, yielding the solute molecule. • The carrier then returns to the original site to accept a new molecule. • There are two type of carrier mediated transport system. - Facilitated diffusion - Active transport I. FACILITATED DIFFUSION • Facilitated diffusion is a form of carrier transport that does not require the expenditure of cellular energy. • Carriers are numerous in number and are found dissolved in cell membrane. • The driving force is concentration gradient, particles move from a region of high conc. to low concentration. • The transport is aided by integral membrane proteins. 12
  • 15. GM Hamad • Facilitated diffusion mediates the absorption of some simple sugars, steroids, amino acids and pyrimidines from the small intestine and their subsequent transfer across cell membranes. II. ACTIVE TRANSPORT • Requires energy, which is provided by hydrolysis of ATP for transportation. • More commonly, metabolic energy is provided by the active transport of Na+ or is dependent on the electrochemical gradient produced by the sodium pump, Na+ /K+ ATPase (secondary active transport). • PRIMARY ACTIVE TRANSPORT - Direct ATP requirement - The process transfers only one ion or molecule and only in one direction. Hence, called as uniport. - E.g. Absorption of glucose. - ABC (ATP Binding Cassette) transporters • SECONDARY ACTIVE TRANSPORT - No direct requirement of ATP - The energy required in transporting an ion aids transport of another ion or molecule (co-transport or coupled transport) either in the same direction or opposite direction. - 2 types: ▪ Symport (co-transport) ▪ Antiport (counter transport) 6. ENDOCYTOSIS • It is a process in which cell absorbs molecules by engulfing them. • Also termed as vesicular transport. • It occurs by 3 mechanisms: - Phagocytosis - Pinocytosis - Transcytosis I. PHAGOCYTOSIS • Phagocytosis refers to the engulfment of larger particles or macromolecules, generally by macrophages. II. PINOCYTOSIS • It is a form of endocytosis in which small particles are brought to the cell, forming an invagination. • These small particles are suspended in small vesicles. • It requires energy in the form of ATP. 13
  • 16. GM Hamad • It works as phagocytosis, the only difference being, it is non-specific in the substances it transports. • This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients. III. TRANSCYTOSIS • It is the process through which various macromolecules are transferred across the cell membrane. • They are captured in vesicles, on one side of the cell and the endocytic vesicle is transferred from one extracellular compartment to another. • Generally used for the transfer of IgA and insulin. FACTORS AFFECTING DRUG ABSORPTION 1. Pharmaceutical factors A. Physicochemical factors B. Formulation factors 2. Patient related factors A. Physiological factor B. Clinical factor 1. PHARMACEUTICAL FACTORS A. PHYSICO -CHEMICAL FACTORS • Drug solubility and dissolution rate. • Particle size & effective surface area. • Polymorphism & amorphism. • Salt form of the drug • Lipophilicity of the drug • pKa of the drug & pH • Drug stability I. DRUG SOLUBILITY AND DISSOLUTION RATE • Rate determining process in the absorption of orally administered drugs are: - Rate of dissolution - Rate of drug permeation through the bio-membrane. • Hydrophobic: Rate Determination Step → Dissolution - E.g: Griseofulvin, spironolactone • Hydrophilic: Rate Determination Step → Permeation rate limited. - E.g: Cromolyn sodium or neomycin II. PARTICLE SIZE AND EFFECTIVE SURFACE AREA • Particle size and surface area of a solid drugs are inversely related to each other. 14
  • 17. GM Hamad • Hydrophobic drugs → micronization → greater surface area → rapid dissolution. - E.g: griseofulvin, spironolactone • Some of the Hydrophobic drugs → micronization → decrease in effective surface area → fall in dissolution rate. - Causes ▪ Adsorption of air to surface ▪ Particle reaggregation ▪ Surface charge - E.g: aspirin, phenacetin - In that case add Surfactants: tween 80, hydrophilic diluents: PEG, PVP, Dextrose. III. POLYMORPHISM AND AMORPHISM • POLYMORPHISM - A substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as polymorphism. ▪ Enantiotropic polymorph: Sulphur ▪ Monotropic polymorph: glyceryl stearate - Depending on their relative stability, one of the several polymorphic forms will be physically more stable than the others. - Stable polymorphs ▪ Highest MP ▪ Lowest energy state ▪ Least aqueous solubility - Metastable polymorphs ▪ Low MP ▪ Higher energy state ▪ High aqueous solubility - E.g. The vitamin riboflavin exists in several polymorphic forms, and these have a 20-fold range in aqueous solubility. • AMORPHISM - These drugs can exist with no internal crystal structure. - Such drug represents the highest energy state and can be considered as super cooled liquids and thus have greater solubility. E.g. Novobiocin. 15
  • 18. GM Hamad - Thus, the order of dissolution and hence absorption for different solid dosage forms is amorphous > meta-stable > stable. IV. SALT FORM OF THE DRUG • Salt of weak acid and weak bases have much higher aqueous solubility than the free acid or base. • Therefore, if the drug can be given as a salt, the solubility can be increased, and the dissolution thus can be improved. V. DRUG pKa, LIPOPHILICITY AND GI pH pH PARTITION THEORY • Explains influences of GI pH drug pKa on the extent of drug transfer or drug absorption (Ka – absorption rate constant). • The process of absorption of drug compounds of molecular weight greater than 100 Daltons transported across the bio-membrane by passive diffusion depend upon the following factors: - Dissociation constant of the drug i.e. pKa of the drug - Lipid solubility of the unionized drug i.e. Ko/w - pH at the absorption site • The amount of drug that exist in unionized form is a function of dissociation constant(pKa) of the drug and pH of the fluid at the absorption site. • PKa of the drug - Dissociation or ionization constant: ▪ pH at which half of the substance is ionized and half is unionized. • pH of medium - Affects ionization of drugs: ▪ Weak acids → best absorbed in stomach. ▪ Weak bases → best absorbed in intestine. • pH-partition Hypothesis - Unionized Drug: Higher Absorption - Ionized Drug: Low Absorption • FOR WEAK ACIDS % Drug Ionized = 10pH − pKa 1 + 10pH − pKa X 100 • FOR WEAK BASES 16
  • 19. GM Hamad % Drug Ionized = 10pKa − pH 1 + 10pKa − pH X 100 PREDICTION BASED ON THEORY Drugs PKa PH / Site of absorption For Acidic Drugs Very weak acids E.g. pentobarbital, Hexobarbital > 8 Unionized at all pH values; Absorbed along the entire length of GIT. Moderately weak acids E.g. aspirin, Ibuprofen 2.5 – 7.5 Unionized in gastric pH and ionized in intestinal pH; better absorption from stomach. Stronger acids E.g. disodium cromoglycate < 2.0 Ionized at all pH values; Poorly absorbed from GIT. For Basic Drugs Very weak bases E.g. theophylline, Caffeine < 5.0 Unionized at all pH values; Absorbed along entire GIT. Moderately weak bases E.g. codeine 5 – 11 Ionized at gastric pH, unionized at intestinal pH; better absorption from intestine. Stronger bases E.g. guanethidine > 11 Ionized at all pH values; Poorly absorbed from GIT. VI. LIPOPHILICITY • Only unionized drug having sufficient lipid solubility is absorbed into systemic circulation. • So, drug should have sufficient aqueous solubility to dissolve in the fluids at the absorption site and lipid solubility high enough to facilitate the partitioning of the drug in lipoidal membrane and into systemic circulation. VII. DRUG PERMEABILITY • Three major drug properties which affects drug permeability: - Lipophilicity - Polarity of the drug - Molecular size of the drug VIII. DRUG STABILITY • Two major stability problems are: 17
  • 20. GM Hamad - Degradation of the drug into inactive form. - Interaction with one or more component either of the dosage form or those present in the GIT to form a complex that is poorly soluble. B. FORMULATION FACTORS • Disintegration time • Manufacturing variables • Different Oral Dosage forms • Pharmaceutical ingredients/ Excipients • Product age and storage condition I. DISINTEGRATION TIME • It Is of particular importance in case of solid dosage forms like tablets and capsules. • Rapid disintegration is important in the therapeutic success of solid dosage form. • Sugar coated tablets have long disintegration time (DT). • DT is directly related to the amount of binder present and the compression force of a tablet. • After disintegration, granules deaggregate into tiny particles → dissolution faster. II. MANUFACTURING VARIABLES a) METHOD OF GRANULATION • Wet granulation was thought to be the most conventional technique. • Direct compressed tablets dissolve faster. • Agglomerative phase of communition → superior product. b) COMPRESSION FORCE • Higher compression force → increased density and hardness → decreased porosity and penetrability → reduced wettability → in turn decreased DR. • Also causes deformation, crushing → increased effective surface area → increased dissolution rate (DR). c) INTENSITY OF PACKING OF CAPSULE CONTENTS • Tightly filled capsules-diffusion of GI fluids → high pressure → rapid bursting and dissolution of contents. • Opposite also possible → Poor drug release due to decreased pore size and poor penetrability of GI fluids. III. ABSORPTION OF DIFFERENT ORAL DOSAGE FORMS • Different Types 18
  • 21. GM Hamad - Solution - Suspension - Tablets - Capsules - Enteric Coated Tablet - Powders • Order of absorption Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets > Enteric Coated Tablet > Sustain Release Tablet a) SOLUTION • Aqueous solutions, syrups, elixirs, and emulsions do not present a dissolution problem and generally result in fast and often complete absorption as compared to solid dosage forms. b) SOLID SOLUTIONS • The solid solution is a formulation in which drug is trapped as a solid solution or monomolecular dispersion in a water-soluble matrix. Although the solid solution is an attractive approach to increase drug absorption, only one drug, griseofulvin, is currently marketed in this form. c) SUSPENSIONS • A drug in a suspension is in solid form but is finely divided and has a large surface area. Drug particles can diffuse readily between the stomach and small intestine so that absorption is relatively insensitive to stomach emptying rate. • Adjusting the dose to a patient’s needs is easier with solutions and suspensions than with solid dosage forms. Liquid dosage forms, therefore, have several practical advantages besides simple dissolution rate. • However, they also have some disadvantages, including greater bulk, difficulty in handling, and perhaps reduced stability. d) TABLETS AND CAPSULES • These formulations differ from each other in that material in capsules is less impacted than in compressed tablets. Once a capsule dissolve, the contents generally disperse quickly. The capsule material, although water soluble, can impede drug dissolution by interacting with the drug, but this is uncommon. • Tablets generally disintegrate in stages, first into granules and then into primary particles. As particle size decreases, dissolution rate increases due to increased surface area. IV. PHARMACEUTICAL INGREDIENTS/EXCIPIENTS 19
  • 22. GM Hamad • More the number of excipients in dosage form, more complex it is and greater the potential for absorption and bioavailability problems. • Changing an excipient from calcium sulfate to lactose and increasing the proportion of magnesium silicate, increases the activity of oral phenytoin. • Absorption of tetracycline from capsules is reduced by calcium phosphate due to complexation. • Most of these types of interactions were reported some time ago and are unlikely to occur in the current environment of rigorous testing of new dosage forms and formulations. • Excipients commonly used: - Vehicle - Diluents - Binders & granulating agent - Disintegrants - Lubricants - Suspending agents/viscosity agent - Surfactants - Bile salts - Colorants V. PRODUCT AGE AND STORAGE CONDITIONS • Aging and alteration in storage condition changes the physiochemical properties of a drug which adversely affects bioavailability. • During storage - Metastable form → Stable form - Change in particle size - Tablet → harden / soften • E.g. - Prednisone tablet containing lactose as a filler, high temp and high humidity resulted in harder tablet that disintegrated and dissolve slowly. 2. PATIENT RELATED FACTORS A. PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTION I. MEMBRANE PHYSIOLOGY • Nature of Cell Membrane • Transport Processes II. GASTERO-INTESTINAL PHYSIOLOGY a) GASTRIC EMPTYING RATE • Anatomically, a swallowed drug rapidly reaches the stomach. 20
  • 23. GM Hamad • Eventually, the stomach empties its contents into the small intestine. Because the duodenum has the greatest capacity for the absorption of drugs from the GI tract, a delay in the gastric emptying time for the drug to reach the duodenum will slow the rate and possibly the extent of drug absorption, thereby prolonging the onset time for the drug. • Some drugs, such as penicillin, are unstable in acid and decompose if stomach emptying is delayed. Other drugs, such as aspirin, may irritate the gastric mucosa during prolonged contact. • Gastric emptying rate is faster in case of solution & suspensions than solid and non-disintegrating dosage forms. • Factors that influence gastric emptying rate are: - Volume of meal - Composition of meal - Physical state and viscosity of meal - Temperature of meal - Gastrointestinal pH - Electrolyte and osmotic pressure - Body posture - Emotional state b) INTESTINAL MOTILITY • Normal peristaltic movements mix the contents of the duodenum, bringing the drug particles into intimate contact with the intestinal mucosal cells. • The drug must have a sufficient time (residence time) at the absorption site for optimum absorption. In the case of high motility in the intestinal tract, as in diarrhea, the drug has a very brief residence time and less opportunity for adequate absorption. c) DRUG STABILITY IN GIT • Metabolism or degradation by enzymes or chemical hydrolysis may adversely affect the drug absorption and thus reduces bioavailability. • Destruction in gastric acid. • Generally, a problem with orally administered drugs. d) INTESTINAL TRANSIT • Long intestinal transit time is desirable for complete absorption of drug e.g. for enteric coated formulation and for drugs absorbed from specific sites in the intestine. • Peristaltic contraction promotes drug absorption by increasing the drug membrane contact and by enhancing dissolution especially of poorly soluble drugs. 21
  • 24. GM Hamad • Influenced by food, disease and drugs. e.g. metoclopramide which promotes intestinal transit and thus enhance absorption of rapidly soluble drugs while anticholinergic retards intestinal transit and promotes the absorption of poorly soluble drugs. e) BLOOD FLOW TO GIT • Once the drug is absorbed from the small intestine, it enters via the mesenteric vessels to the hepatic-portal vein and the liver prior to reaching the systemic circulation. Any decrease in mesenteric blood flow, as in the case of congestive heart failure, will decrease the rate of drug removal from the intestinal tract, thereby reducing the rate of drug bioavailability. • GIT has higher perfusion rate because it is extensively supplied by blood capillary network. • Therefore, help in maintaining sink conditions and concentration gradient for drug absorption by rapidly removing of drug from site of action. • Blood flow is important for actively absorption of drugs. • Highly permeable drugs or drugs that absorbed through pores –GI perfusion is rate limiting while the drugs with poor permeability GI perfusion is not important. • Perfusion increases after meals and persist for few hours, but absorption is not affected. f) EFFECT OF FOOD • The presence of food in the GI tract can affect the bioavailability of the drug from an oral drug product. • Digested foods contain amino acids, fatty acids, and many nutrients that may affect intestinal pH and solubility of drugs. The effects of food are not always predictable and can have clinically significant consequences. Some effects of food on the bioavailability of a drug from a drug product include: - Delay in gastric emptying - Stimulation of bile flow - A change in the pH of GI tract - An increase in splanchnic blood flow - A changed luminal metabolism of the drug substance - Physical or chemical interaction of the meal with the drug product or drug substance. 22
  • 25. GM Hamad • The absorption of some antibiotics, such as penicillin and tetracycline, is decreased with food, whereas other drugs, particularly lipid-soluble drugs such as griseofulvin and metaxalone, are better absorbed when given with food containing a high fat content. • Propranolol plasma concentrations are larger after food than in fasted subjects. This may be an interaction with the components of food. III. AGE • In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults. • In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial overgrowth in small intestine. B. CLINICAL FACTORS I. DISEASE STATE • Several disease state may influence the rate and extent of drug absorption. • Three major classes of disease may influence bioavailability of drug. - GI diseases - CVS diseases - Hepatic diseases a) GI DISEASES • GI Infections - Celiac diseases: Characterized by destruction of villi and microvilli. Abnormalities associated with this disease are increased gastric emptying rate and GI permeability, altered intestinal drug metabolism. • Crohn’s disease - Altered gut transit time and decreased gut surface area and intestinal transit rate. • GI surgery - Gastrectomy may cause drug dumping in intestine, osmotic diarrhea and reduce intestinal transit time. b) CVS DISEASES • In CVS diseases blood flow to GIT decrease causing decreased drug absorption. 23
  • 26. GM Hamad c) HEPATIC DISEASES • Disorders like hepatic cirrhosis influences bioavailability of drugs which undergoes first pass metabolism. II. DRUGS a) ANTICHOLINERGIC • Anticholinergic drugs in general may reduce stomach acid secretion Propantheline bromide is an anticholinergic drug that may slow stomach emptying and motility of the small intestine. Slower stomach emptying may cause delay in drug absorption b) METOCLOPRAMIDE • Metoclopramide is a drug that stimulates stomach contraction, relaxes the pyloric sphincter, and, in general, increases intestinal peristalsis, which may reduce the effective time for the absorption of some drugs. c) ANTACIDS • Antacids containing aluminum, calcium, or magnesium may complex with drugs such as tetracycline, ciprofloxacin, and indinavir, resulting in a decrease in drug absorption. 24
  • 27. GM Hamad BIOLOGICAL HALF LIFE & VOLUME OF DISTRIBUTION HALF LIFE • The time needed to decrease the body drug level by one half of its initial level. If the concentration is reduced due to a physiological process, i.e., biotransformation then, this half life is called as elimination or biological half life. • The half life is the time required for the body to eliminate one half of the drug which it contains. The elimination half life is a function of both, the clearance and the volume of distribution of the drug. It is the characteristic of exponential decay where the time required for a given fraction of drug to disappear is always the same, regardless of the time or concentration at which one begins measurements. • The biological half life is not the time for the response to decline by 50%, since the requirement for a threshold concentration, latency of drug response and other factors cause a non-parallelism between blood concentration and pharmacological response intensity. • The half life is used to determine the time required for the body to eliminate by metabolizing, or excretion or by both, one half of the initial concentration of drug in blood. OTHER TYPES OF HALF LIFE • Besides the elimination half life, the other types of half life are as follows: ABSORPTION HALF LIFE • It is the time to reduce drug concentration at absorption site due to absorption by one half of its initial concentration. DISTRIBUTION HALF LIFE • The time required to reduce concentration of drug to half of its initial concentration due to the distribution of drug is called as distribution half life. PHYSICAL HALF LIFE 25
  • 28. GM Hamad • This half life pertains to the radiopharmaceuticals. Physical half life is the time to decrease the concentration of a substance to half due to physical decay. For instance, the radiopharmaceutical decays physically and the time at which its concentration is reduced to half of its initial concentration is the physical half life. EFFECTIVE HALF LIFE • When a radiopharmaceutical is administered, its concentration decays due to its physical disintegration as well as due to its biotransformation. Effective half life combines both the elimination half life and the physical half life of a radiopharmaceutical. ZERO AND FIRST ORDER HALF LIFE • Drug concentration may decay by two modes, first order half life or by zero order half life. FIRST ORDER HALF LIFE • Half life of the first order process is a constant for a given rate process hence the half life is the time required [C]t (concentration at time t) to become equal to one half of [C]0 (the initial value at zero time). The first order half life can be calculated by the formula: t½ = 0.693 k • This formula has been derived from the equation of the graph to describe the first order kinetics. The basis for this equation is Y = mx + b, where Y is the concentration, m is the slope (or rate constant) of the curve and b is the y-intercept. • Log natural (Ln) is included because the blood level time curve is a straight line on the graph between Ln of concentration versus time. Ln[C]t − Ln[C]0 = −kt This equation can be arranged in the following several ways −Ln[C]t = −kt + Ln[C]0 ⇛ −Ln [C]t [C]0 = kt ⇛ Ln [C]0 [C]t = kt • By definition half life is the time when the concentration is half of the initial concentration, thus, at this time, in equation, the [C]t becomes 26
  • 29. GM Hamad ½ [C]0 and t as t½. Ln [C]0 1 2 [C]0 = kt½ Rearranging the above equation yields the following equation. Ln 2[C]0 [C]0 = kt½ ⇛ Ln 2 k = t½ • This equation represents one of the ways to calculate the first order half life using the rate constant determined from a first order graph of the data. A drug being eliminated by a first order process will have a half life which is constant and independent of the initial concentration or dose of the drug. ZERO ORDER HALF LIFE • The half life of zero order process is not like that discussed for the first order process. • Applying the definition of half life to the zero-order process, equation yields as: [C]t = −kt + [C]0 • At half life, the [C]t in equation becomes ½[C]0 and the t as t½, thus the above equation for zero order becomes as following. [C]0 2 − [C]0 = −kt½ ⇛ − [C]0 2k = −t½ ⇛ t½ = 0.5[C]0 k • Where C0 is the initial concentration, k is the rate constant for the zero- order process. The equation indicates that the half life is not independent of the initial concentration. Factually, lager the initial concentration, the greater is the half-life. The difference can be used to distinguish between zero and first order process by varying the initial concentration (or order) and measuring the resulting half life. METHOD OF DETERMINATION 1. Direct graphical method: - Half life of a drug can be estimated by direct reading the time needed for concentration to decrease by one half from any point on the log concentration time plot. 27
  • 30. GM Hamad 2. From the slope of the terminal log concentration time curve: - The slope of the curve is the elimination rate constant. Using the formula of first order half life, half life can be calculated. 3. Calculation from urine data: - Half life is also calculated from the urine data assuming that the renal clearance of drug is constant, the excretion rate parallels the plasma concentration. The half life can be calculated by urine concentration data. But practically, urine concentration data gives usually poor estimate due to incomplete bladder emptying and inability to collect samples frequently. RELATIONSHIP OF ELIMINATION HALF LIFE WITH CLEARANCE, VOLUME OF DISTRIBUTION • The clearance and volume of distribution are the two independent pharmacokinetic parameters which determine elimination half life and thus, the half life. These two are the dependent parameters. C𝑙 = K x Vd ⇛ C𝑙 Vd = k ⇛ 0.693 t½ SIGNIFICANCE OF HALF LIFE 1. Reflects the rate of drug elimination, similar to the elimination rate constant. Drug that have a short half life (i.e., having larger elimination rate constant) are readily eliminated from the body. 2. Half life is used in deciding the appropriate dosage regimen. Drugs with shorter half life require frequent dosing during multiple administration. 3. It gives the estimate of the rate of drug removal from the body. 4. It indicates the efficiency of the elimination process. Thus, change in half life will reflect change in elimination organ functions such as liver 28
  • 31. GM Hamad biotransformation or the excretion in kidney. It is thus, a prime measure for the dosage adjustment in disease status. 5. A drug with brief half life requires more frequent dosage that the drug with long half life. 6. The drug having half-life between 3 to 4 hours are the good candidates for control release formulations. 7. Drugs reach to steady state concentration in approximately 5 half lives. 8. A drug is completely eliminated after 10 half life and usually negligible within 7 half lives. 9. Provides the basis for classification of the drugs having ultra-fast, slow and very slowly disposition drugs. The ultra-fast disposition (UFD) drugs has half life of less than 1-hour, slow disposition (SD) drugs have half life of 8-24 hours and that very slow disposition (VSD) drugs have the half life of more than 24 hours. FACTORS AFFECTING HALF LIFE • Half life of a drug is affected by any factor which modifies the drug metabolism and excretion. The factors can be categorized into patient related, drug related and combinedly related to the drug as well as to the patient. Patient related factors include age, genetic, renal insufficiencies, hepatic insufficiencies, urine pH, gender, nutritional status, emotional status, hormonal level, body temperature, volume of distribution, etc. • Factors related to drug include co-administered drug-drug interaction, inhibition of drug metabolism, stimulation of drug metabolism via increased enzyme activity or via enzyme induction, therapy duration (enzyme exhausted). COMBINED PATIENT AND DRUG RELATED FACTORS • Combined patient and drug related factors include the pKa of acidic or basic drugs, affinity for protein binding, tissue storage, volume of distribution. RENAL MALFUNCTION • The renal clearance is altered if there is any disease, malfunctioning or insufficiencies of kidney. • When renal clearance decreases, the half life is increased and vice versa. HEPATIC DISEASE 29
  • 32. GM Hamad • Liver is the site of metabolism for most of the drugs. When the liver is not functioning properly, the rate of drug elimination will be decreased due to a decreased metabolism leading to increase in half life of the drug. URINARY pH • pH changes leads to altered rate of drug excretion and kidney reabsorption of the drug. Basic drugs are rapidly excreted through acidic urine and vice versa. This of course will affect the half life. AGE • As rate of metabolism are different in various stage of human age, the half life obviously varies in different age groups. In children, liver is not well developed so the metabolism rate is slow. In elder patients, the system gets exhausted and thus the rate is slow. GFR is also gradually decreased after the age of 30 years. AFFINITY FOR PROTEIN BINDING • Customarily, the drug bound with protein is not available for drug metabolism and excretion thus leading to an increased half life. However, drugs can be categorized into restrictively cleared and non- restrictively cleared drugs. • The restrictive cleared drugs are also known as binding sensitive drugs. The bound drugs not able to diffuse through cell membrane, and thus not able to reach site of metabolism and excretion. Thus for such drugs, increase in the free drug concentration in the blood will make more drug available for hepatic extraction as well as for renal excretion. • Non-restrictively cleared drugs are also known as binding-insensitive drugs. These drugs are extracted by the liver with greater rate regardless of bound to protein or free. The elimination half life of such drug is not significantly affected by a change in the degree of protein binding. The drug is removed from the plasma binding sites during the circulation through the liver by inducing a conformation change in the protein, weakening the process of binding and subjecting the drug to metabolism. The drugs activity secreted though the renal route are binding insensitive. TISSUE STORAGE 30
  • 33. GM Hamad • Certain drugs have an affinity for adipose tissue and thus are stored for a prolonged time period leading to an increased half life. CO-ADMINISTRATION OF DRUG AND DRUG INTERACTION • Co-administrated drugs may alter the half life of one another drug by: - Competing for protein binding i.e., warfarin and phenylbutazone. - Competing for metabolizing enzyme if both are metabolized by the same enzyme - Altering the urinary pH - Enzyme inhibition - increases the half life - Enzyme induction - decrease the half life. GENETIC FACTORS • The genetic factors contribute substantially to the larger difference among the individuals for fate of drug metabolism and clearance of drug. Thus, half life of drug is affected by genetic variations. Some individuals are slow acetylators while others are fast acetylators. VOLUME OF DISTRIBUTION • Half life is the function of both the clearance and the volume of distribution of drug may have large clearance but still have a long half life due to increase value of the volume of distribution. VOLUME OF DISTRIBUTION (Vd) • Volume of distribution is defined as the apparent volume available for the distribution of a drug in body. This parameter indicates the apparent space as volume in body available to contain drug. • Since the values of Vd does not have a true physiologic meaning in terms of an anatomic space, the term “apparent” is used with Vd as prefix. The Vd represents a volume that must be considered in estimating the amount of drug in body from the concentration of drug found in the sampling compartment, i.e. blood. • Since the drug is not distributed equally in all tissues of the body (compartments) due to drug’s different affinities to different tissues, the volume of distribution does not represent a real volume rather represents a hypothetical volume. This volume relates the amount of drug in the body to the plasma concentration by the equation: 31
  • 34. GM Hamad Vd = Db Cp - Where, Db is the drug in body and Cp is the concentration in plasma. • Though the Vd is hypothetical, yet it is influenced by the physicochemical properties and the affinity of drugs to the blood and tissues. The drug lipid solubility which dictates the affinity of drug to tissues and the protein binding, affect Vd. • Vd is an independent pharmacokinetic parameter which does not depends on the other pharmacokinetic parameters. Vd provides an estimate of the drug which does not appear in the plasma or distributed at tissue level. A very high Vd reflects binding of drug with the tissue proteins. RELATIONSHIP OF VD WITH OTHER PHARMACOKINETIC PARAMETERS • The following equation shows the relationship of Vd with other pharmacokinetic parameters, such as elimination rate constant and the clearance. C𝑙 = k x Vd SIGNIFICANCE OF Vd • The Vd is used to calculate a dose of drug required to achieve certain blood concentration (called as the target concentration and abbreviated as CT) as: Dose = CT x Vd • The volume of distribution is a distribution parameter which indicates the extent of distribution. Based on its obtained values, the extent of drug distribution can be classified as: - The widely distributed drugs which show volume of distribution greater than 0.7 L/Kg. - The moderately distributed drug which demonstrates values of the volume of distribution between 0.3-0.7 L/Kg. - Limited distributed drugs having the volume of distribution lesser than 0.3 L/Kg. • As has been mentioned that the Vd is not a true physiologic volume, most of the drugs have an apparent volume of distribution smaller than, 32
  • 35. GM Hamad equal to or several times more than the body mass. It depends on the initial plasma concentration. • Vd is a useful parameter in considering the relative amount of drug in the vascular and in the extravascular tissues. • Magnitude of the apparent Vd is a useful indicator for the amount of drug outside the sampling compartment which is usually blood. The volume of distribution at steady-state (Vd(ss)) is important for determining the relevance of changes in the extent of distribution of drug in the presence of diseases. ALTERED Vd • For each drug, the apparent Vd is a constant. In certain pathologic cases however, the Vd for the drug may be altered if the distribution of the drug is changed due to the change in the total body water and total extracellular water. If these increases, (as in the case of edematous condition), a very larger Vd results for a drug with more water solubility. EXCESSIVELY LARGER Vd • Drugs may exhibit very large values of Vd which exceed all the volumes available in the body, e.g., chloroquine Vd is about 115 L/ kg. Such drugs show concentration of drug specifically in one or more tissues. Chloroquine concentrates in liver 1000 times more than in plasma. • Even wide range of Vd values are expected for the drugs exhibit a non- uniform distribution in the body with variations due to difference in their passing through membranes and their lipid/water solubility. • The highest concentrations of drugs are often present in the kidney, liver, and intestine which usually reflect the amounts of drug being excreted. LARGER Vd • A larger Vd occurs if the drug is extensively distributed in peripheral tissues and organs and resulting into a smaller inter-vascular concentration. This means that the drug with a larger apparent Vd are more concentrated in extravascular tissues and less concentrated intravascularly. A Vd between 30 and 50 liters, corresponds to drug distribution in the total body water. • Binding of the drug with peripheral tissue or its proteins, results into an increased Vd. The protein bound drugs showing larger Vd when 33
  • 36. GM Hamad displaced from the protein, do not show any clinically relevant consequence. SMALLER Vd • If a drug is highly bound to plasma proteins, or remains in the vascular regions, it will result in a smaller apparent Vd. A value of Vd in the range of 3-5 liter (in an adult) would indicate that the drug is in the vascular compartment since this is the value of plasma volume. • For polar drugs with low lipid solubility, the apparent Vd is generally small. Protein bound drugs having smaller Vd, produce pharmacodynamic effects when displaced from plasma protein. • In two compartment model, Vdss reflects the true distribution volume occupied by the plasma and the tissue pool when steady state is achieved. This volume is used to calculate the loading drug dose necessary to upload the body to a desired plasma drug concentration. CALCULATION OF VOLUME OF DISTRIBUTION • The volume of distribution after extravascular administration is calculated as Vd (area) by the following equation. Vd(area) = Dose AUC . β - Where, AUC is total area under the blood level time curve, beta is rate of elimination. • The Vd(ss) is the volume of distribution after IV administration and it represent the volume in which a drug appears to be distributed during steady-state if drug existed throughout the volume at the same concentration as in the measured fluid. The Vd(ss) is generally calculated by non-compartmental approach as: Vd(ss) = DoseIV . AUMC (AUC)2 - Where AUC is the total area under the curve and AUMC is the area under the first moment of the plasma concentration-time curve. The value of Vd(ss) is generally smaller than the Vd area. 34
  • 37. GM Hamad DRUG CLEARANCE INTRODUCTION • Synonyms: Systemic clearance, body clearance, total clearance. • Total clearance represents sum of clearances by the various organs that contribute to elimination of drug. C𝑙Total = C𝑙Renal + C𝑙Hepatic + C𝑙Lungs • Clearance describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved. • Clearance can be defined as “The volume of fluid cleared of drug from the body per unit time.” • Clearance is a proportionality constant describing a relationship between rate of elimination (as amount per unit time) at a given time and its corresponding concentration in fluid at that time. • It may be regarded as, “the volume of blood or plasma (depending upon the fluid used for drug assay) from which the drug appears to be removed per unit of time to account for its elimination.” • Example: clearance considers that a certain portion or fraction (percent) of the distribution volume is cleared of drug over a given time period. • Clearance is a pharmacokinetic parameter that describes drug elimination from a hypothetical well stirred compartment containing uniform drug distribution. • For first order elimination process, clearance is constant. Clearance applies to all elimination rate processes, regardless of the mechanisms for elimination. It may have values that are not physiological. • Unit: The unit of clearance are milliliters per minute (ml/min, ml/min.Kg) or liters per hour (L/h, L/h.Kg). IMPORTANCE OF CLEARANCE • Clearance is the one parameter that determines the maintenance dose rate required to achieve a desired plasma concentration. Dosing rate = clearance x desired plasma concentration 35
  • 38. GM Hamad MECHANISIM OF CLEARANCE • Renal excretion • Hepatic excretion • Minor clearance through lungs and skin. RENAL EXCRETION • Renal excretion is the major route of elimination for many drugs. For example, water soluble and low molecular weight drugs, or the drugs that are slowly bio-transformed by the liver. • Drug excretion from the kidney involves combination of the following: - Glomerular filtration - Active tubular secretion - Tubular reabsorption HEPATIC CLEARANCE • Hepatic clearance is the volume of blood that perfuses the liver which is cleared of drug per unit time. • Hepatic clearance involve Biotransformation or Drug Metabolism (Phase I and Phase II). CLEARANCE MODELS • Model Independent • Model dependent or Compartment Model • Physiologic Model MODEL INDEPENDENT • This is a non-compartmental approach used to calculate Clearance. This model does not require any assumption for a specific compartment model. • Therefore, Clearance can be determined directly from the Plasma-Time concentration curve using: 𝐶𝑙 = ∫ 𝐷0 𝐶 𝑝 𝑑𝑡 ∞ 0 • Since there is no compartment considered, therefore, [AUC]0 ∞ = ∫ 𝐶 𝑝 𝑑𝑡 ∞ 0 , Replacing this in the above equation gives: 𝐶𝑙 = 𝐷0 [AUC]0 ∞ 36
  • 39. GM Hamad MODEL DEPENDENT OR COMPARTMENTAL MODEL • Model Dependent considers compartmental approach and the clearance is calculated by assuming volume of distribution and elimination rate constant. C𝑙T = 𝑘V 𝐷 PHYSIOLOGIC MODEL • This model is organ specific. Clearance may be defined as the fraction of blood volume containing drug that flows through the organ and is eliminated of drug per unit time. OR • Clearance is the product of the blood flow (Q) to the organ and the extraction ratio (ER). C𝑙Organ = Q(ER) • If the drug concentration in the blood (Ca) entering the organ is greater than the drug concentration of blood (Cv) leaving the organ, then some of the drug has been extracted by the organ. • The ER is Ca – Cv divided by the entering drug concentration (Ca), as shown: ER = Ca − Cv Ca Substituting in the previous equation C𝑙Organ = Q ( Ca − Cv Ca ) CALCULATION OF CLEARANCE • Body clearance (ClB) after E/V route is: C𝑙B = 𝐹 . 𝐷𝑜𝑠𝑒 𝐴𝑈𝐶 • For ClB after IV route the fraction of dose absorbed (F) is not included in equation: C𝑙B = 𝐷𝑜𝑠𝑒 𝐴𝑈𝐶 • For ClB after steady state IV infusion: C𝑙B = k0 Css 37
  • 40. GM Hamad • If volume of distribution by area calculated from terminal curve (Vdarea) and rate of elimination (Ke) is known, then ClB is: C𝑙B = 𝑉𝑑 𝑎𝑟𝑒𝑎 ⨯ ke RELATIONSHIP OF CLEARANCE WITH HALF-LIFE • If we know the Clearance, we can determine Half-Life (t½) of a drug through a simple relation: C𝑙T = k ⨯ Vd k = 0.693 t½ Therefore, by substitution C𝑙T = 0.693 𝑉𝑑 𝑡1/2 APPLICATIONS OF CLEARANCE 1. The volume concept is simple and convenient because all drugs are dissolved and distributed in the fluid of the body. 2. Clearance can be computed reliably. 3. It is used to compute other parameters such as dose. 4. It is pharmacokinetic parameter including drug disposition, drug elimination and drug excretion. 5. The values of clearance measured based on plasma clearance could be interpreted physiologically. PHYSIOLOGICAL INTERPRETATION OF THE DRUG CLEARANCE VALUES • The systemic clearance may predominantly represent hepatic clearance. For drugs undergoing extensive biotransformation, systemic clearance mainly reflects the capacity of liver to metabolize these drugs. • The clearance exceeding hepatic blood flow indicates the drug is simultaneously metabolized by liver and extra hepatic site (renal/lungs). For example: anesthetic propofol is cleared of blood through hepatic lungs. • For drugs solely eliminated by glomerular filtration the clearance expected to reflect the GFR. • Lower clearance relative to GFR represent renal clearance with drug re absorption. For example: gentamicin. 38
  • 41. GM Hamad COMPETING TERMINOLOGIES • Metabolism and excretion are the competing terminologies of clearance. EXCRETION • Excretion is the removal of drug from the body. The unit of excretion are amount per unit of time. For example: mg/min. • In excretion the drug may be inactivated but it no longer remains in your body. METABOLISM • Metabolism activates prodrug or inactivates a drug which may remain in the body. 39
  • 42. GM Hamad B Concentration AUC LINEAR AND NON-LINEAR PHARMACOKINETICS LINEAR PHARMACOKINETICS • The linear pharmacokinetics is characterized by 1st order kinetics in distribution and elimination kinetics of a drug. The same order of kinetics is assumed after increase of dose. For example, when the dose of a drug is doubled, the concentration in blood is doubled. • Graphically, linear pharmacokinetics can be demonstrated as given in Figure 1. • Majority of the drugs follows the linear pharmacokinetics. NON-LINEAR PHARMACOKINETICS • Being nonlinear means the effect of increase in one parameter results in disproportional increase, decrease or no change in the other parameter. In pharmacokinetics, the area under the curve (AUC), an absorption parameter when plotted against three graded doses (increased amounts) of drug it may proportionally increase, decrease or remains unchanged. • When the levels of AUC decrease or demonstrates no change with increase in dose is called as the non-linear pharmacokinetics. • Nonlinear pharmacokinetics is the deviations from the linear pharmacokinetic profile of a drug. A Figure 1: Linear Pharmacokinetics, A) Concentration increased linearly with increase in dose and B) Linear correlation between dose and area under the curve (AUC). 40
  • 43. GM Hamad • A few drugs follows the nonlinear pharmacokinetics where an increase in dose causes a nonlinear or disproportional change in blood concentration and thus, area under the curve (AUC). • Non-linearity leads to a higher or lower than the expected rise in concentration or AUC with increased dose, as a result of dose- dependent changes in absorption, distribution and elimination process. Thus, the nonlinear kinetics is also known as capacity-saturation or saturation kinetics. • In non-linear pharmacokinetics, the kinetics of a process dealing with drug deviates from the first order kinetics, which is the most commonly followed in pharmacokinetic processes. In terms of kinetics, this deviation is called as saturation kinetics, Michaelis-Menten of capacity- limited kinetics. CAUSES OF NON-LINEARITY 1. Saturation of process 2. Saturation of transporter 3. Saturation of enzyme 4. Pathologic conditions 5. Drug-induced 6. Disproportional activation of endogenous entities, e.g., ATPase, P-pg PROCESSES INVOLVED IN NON-LINEAR PHARMACOKINETICS • Nonlinear absorption results from saturation of carrier-mediated transport causing lower than expected drug concentration with increase in dose. In absorption, the saturation of pre systemic metabolism in gut wall results in higher than the expected concentration since greater proportion of administered dose survives the hepatic metabolism. For instance, higher doses of salicylates saturate its glycine conjugation in children. • There are three categories of drugs which affect P-gp differently. - Category I drugs can stimulate P-gp in low concentrations while inhibit P-gp at higher concentrations. - Category II drugs can produce dose dependent activation of ATPase. - Category III can inhibit activity of ATPase. • The category I can lead to non-liner absorption/excretion/secretion due to the distribution of P-gp at relevant locations. 41
  • 44. GM Hamad BA • Saturation of plasma protein binding causes nonlinear distribution and occurs when the drug concentration exceeds binding capacity of protein, an effect is pronounced with the basic drugs that bind to alpha-1 acid glycoprotein due to lower concentration of this protein than that of the albumin. However, nonsteroidal anti-inflammatory drugs and valproic acid show nonlinear protein binding with albumin. • Drugs saturating absorption or distribution are few and have no significant effect on clinical dosing. • Saturation of first pass metabolism in liver, respectively results in higher than the expected concentration since greater proportion of administered dose survives metabolism. For instance, higher doses of salicylates saturate its glycine conjugation in children. • Nonlinear elimination occurs with saturation of renal or biliary secretion. Nonlinear elimination occurs for drugs undergoing hepatic metabolism and taken at higher but within the clinical doses. • Incremental dose of penicillin causes saturation of a transporter in renal secretion of the drug leading to its non-linear elimination. • Phenytoin saturates metabolism at upper range of clinical dose while ethanol saturate even at lower dose. INDICATION OF NON-LINEAR PHARMACOKINETICS • In nonlinear elimination, rather than an exponential (first order) decline in the plasma concentration, zero order elimination occurs initially shown by a straight line on the linear plot and convex curve on semilogarithmic graph. • Until the concentration of drug falls sufficiently low, the elimination returns to first order decline because the elimination process will no longer be saturated (Figure 3). Figure 3: Michaelis-Menten kinetics 42
  • 45. GM Hamad A B COMPARISON OF MICHAELIS-MENTEN KINETICS TO OTHER KINETICS ORDERS • The order of kinetics is determined by the graphical method and each order of kinetics gives a specific profile when drawn as concentration against time and Ln-concentration against time (or on semilogarithmic graph paper). • With linear concentration, the first order is a curved line (Figure 4 A), zero order kinetics shows a straight line (Figure 4 C) and the Michaelis- Menten kinetic reflects a rapid decline and then a slow decline due to saturation of the process (Figure 3 A). • When the Ln-transformed concentration data is plotted on ordinary graph (or the semilogarithmic graph is used), the first order becomes a straight line (Figure 4 B) and zero order gives an upward curve in Figure 4 C. • For the Michaelis-Menten kinetics, the line with Ln-transformed concentration yields a slow and then a fast decline (Figure 1 B). The profile in graph Figure 3 B deviates from linearity (zero order) and then becomes linear (first order). INTERPRETATION • In first order kinetics the rate of decline of drug concentration depends on the concentration. In zero-order kinetics, the decline is independent of the drug concentration in the tissue. • Michaelis Menten kinetics is usually applicable to drug elimination where the drug elimination depends on the degree of saturation of the elimination process. In this kinetics, the enzyme involved in drug biotransformation is activated in a manner dependent on the drug concentration. 43
  • 46. GM Hamad C D Equation 1 Equation 2 Equation 3 IMPACT OF NON-LINEARITY ON PHARMACOKINETICS • Due to this complex kinetics, the equations used for linear pharmacokinetics are not applicable, though the concept of compartment model is still applicable. • Application of linear pharmacokinetic models to drug showing nonlinear pharmacokinetics may lead to large or frequent dosing leading to an unexpected accumulation of drug. • Nonlinear pharmacokinetic models require the application of more complicated, enzyme or saturation (Michaelis-Menten) kinetic theory, thus non-linear kinetics is also called as Michaelis-Menten kinetics. PARAMETERS OF NON-LINEAR PHARMACOKINETICS • It is clinically important to know the dose causing saturation of process to avoid drug accumulation and toxicity. • Knowledge of the maximal rate of elimination (Vmax) is important. The Km is the concentration at the half maximal rate of elimination. • The rate constant of decline, Vmax is calculated using equation for slope (m) from the top left straight line on the linear graph. by using the equation 1: Vmax = −m • The C0 (y-intercept) is estimated from the straight line at the top left of the semilogarithmic graph. • The Kel is calculated from the linear terminal slope of the curve on semilogarithmic graph. • The half-life is calculated as: 0.693/Kel. • The Km and Vd are calculated using the equations 2 and 3: km = Vmax kel Vd = Dose C0 Figure 4: First order kinetics (A-B), and Zero order kinetics (C-D) 44
  • 47. GM Hamad APPLICATIONS OF PHARMACOKINETICS IN CLINICAL SITUATIONS Following are the areas where pharmacokinetic are applied: • Individualization of drug dosing regimen - Individual variations in particular patients. • Therapeutic drug monitoring - Involves monitoring of drug conc. in plasma for optimal drug therapy. • Therapeutic window - Drugs having 2-3 therapeutic window, these drugs have narrow therapeutic window TW = Max effective conc. Minimum effective conc. = 20 µg/ml 8 µg/ml = 2.5µg/ml • Candidates of therapeutic drug monitoring • Availability of an assay procedure. FACTORS INFLUENCING DRUG VARIABILITY • Variation in drug absorption • Presence of other drugs • Drug interactions • Genetic differences • Physiological differences • Pathophysiological condition of different people e.g. Immuno- compromised patients. DOSE INDIVIDUALIZATION • Dose individualization is the determination of a sufficient dose which delivers a safe drug. • Concentration that is not toxic not below the minimum effective concentration. • Dose individualization is required for the drugs: - With narrow therapeutic index - Which follow non-linear pharmacokinetics - With saturable in any pharmacokinetic process (e.g. metabolism) 45
  • 48. GM Hamad - Where a relationship exists between blood concentration and desired clinical effect - Where a relationship exist between blood concentration and adverse effects. • Steps to dose individualization are as follows: - Dose adjustment - Pharmacokinetic studies - Empirical dose to patients THERAPEUTIC DRUG MONITORING • TDM is individualization of dose to maintain blood drug concentration within a target therapeutic window. TDM is the measurement of drug concentration with the aim to adjust a dose to deliver concentration within safety window. It is also called therapeutic concentration monitoring. • Pharmacokinetic is an important component of TDM. TDM is required for category of drugs under dose individualization. PROCESS OF THERAPEUTIC DRUG MONITORING I. DEVELOPMENT OF PLASMA PROFILE IN EACH PATIENT • Administering a pre-determined dose of drug based on: - Manufacturer’s recommendation - Patient’s condition - Presence of other condition / disease state - Previous experience of professional with the drug. • Collection of blood samples • Determination of drug conc. in each sample • Plasma profile and pharmacokinetic model development. II. OBSERVATION OF CLINICAL EFFECTS OF DRUGS IN PATIENTS • Incorrect assay methodology • Problem with patient compliance III. DEVELOPMENT OF DOSAGE REGIMEN Following are the methods to design dosage regimen: • EMPERICAL DOSAGE REGIMEN - It is designed by physician based on empirical clinical data, personal experience and clinical observation. • INDIVIDUAL DOSAGE REGIMEN 46
  • 49. GM Hamad - It is based on the pharmacokinetics of drugs in the individual patient. - Suitable for hospitalized patients. • DOSAGE REGIMEN BASED ON POPULATION AVERAGES - It is based on one of two models ▪ FIXED MODEL • Population average pharmacokinetic parameters are used directly to calculate dosage regimens. ▪ ADAPTIVE MODEL • Based on both population average pharmacokinetic parameters of the drug as well as patient variable such as weight. DOSE ADJUSTMENT IN INFANTS & CHILDREN • In children pharmacokinetics and pharmacodynamics of most of the drugs are unknown. There is varied body composition in different age groups. Different age groups require different doses. • There is different liver maturity – conjugative enzymes are absent. • According to FDA guidelines for industry 2000: Parameter Age Newborn infant Birth to 28 days Infant 28 days to 23 months Young child 2 to 5 years Older child 6 to 11 years Adolescent 12 to 18 years Adult Above 18 years • Infants have five immature pharmacokinetics: 1. Drug absorption 2. Renal excretion 3. Hepatic metabolism 4. Protein binding of drugs 5. Blood brain barrier • Kidney function is 30 – 50% lesser than adult based on activity per unit body weight. Reduced protein binding with albumin. Doses are required to be adjusted based on half-life by taking into consideration of age and body surface area. 47
  • 50. GM Hamad DOSE ADJUSTMENT IN ELDERY PATIENTS In elderly or Geriatrics (age >65) patients there is: CHANGES IN DRUG ABSORPTION • Decline in splanchnic blood flow • Altered GI motility • Increase in gastric pH • Alteration in gastrointestinal absorptive surfaces CHANGES IN DRUG DISTRIBUTION • Decrease albumin • Decrease protein binding • Decreased body fat • Decreased volume of distribution • Decreased muscle mass CHANGES IN METABOLISIM AND EXCRETION • Decreased glomerular filtration • Decreased renal plasma flow • Decreased cardiac output • Decreased breathing capacity. All of the above changes leads to age dependent verified drug concentration which may lead to therapeutic failure or adverse effect or toxicity. DOSE ADJUSTMENT IN OBESE PATIENTS • In obesity, following are the changes: - Body weight exceeds ideal body weight by 20% - Body mass index (BMI) > 30 – 39.9 - Greater accumulation of fat tissues compared to muscle tissue causing lower proportion of total body water. • These leads to changes in Vd – Vd is increased. • Altered pharmacokinetic due to distributional changes because of drug partitioning of drug from aqueous to fat environment. Also, changes in the liver and cardiovascular conditions. Thus, accumulation occurs at normal dose. BMI = [ Weight (lb) Height (inch)2 ] X 703 BMI = [ Weight (kg) Height (cm)2 ] X 10,000 48
  • 51. GM Hamad LEAN BODY WEIGHT LBW (males) = 50kg + 2.3kg for each inch over 5ft. LBW (females) = 45.5kg + 2.3kg for each inch over 5ft. Terms BMI Values Underweight < 18.5 Normal 18.5 – 24.9 Overweight 25 – 29.9 Obese 30 – 39.9 Extreme obesity > 40 DOSE ADJUSTMENT IN PREGNANCY • Little information is available in literature. • Plasma concentration of certain drugs may reduce during pregnancy. • Example: phenytoin and phenobarbitone. DOSE ADJUSTMENT IN DISEASE STATES • Diseases alter the drug concentrations due to change in pharmacokinetic processes. - In renal disease, drug clearance is reduced and the half-life is prolonged. - Liver diseases impairs clearance of drugs which depends upon bioconversion to more water-soluble compounds. - CHF can cause elevated drug levels for drug dependent on hepatic metabolism for clearance. 49
  • 52. GM Hamad BIOAVAILABILITY AND BIOEQUIVALENCE INTRODUCTION • Bioavailability is the total amount of an intact drug available systematically after administration of the drug. It is the relative amount of an administered drug reaching to general circulation and the rate at which it occurs. PURPOSE OF BIOAVAILABILITY STUDIES • Bioavailability studies are performed for both approved active drug ingredients and therapeutic moieties not yet approved for marketing by the FDA. • New formulations of active drug ingredients must be approved by the FDA before marketing. • In approving a drug product for marketing, the FDA ensures that the drug product is safe and effective for its labeled indications for use. • Moreover, the drug product must meet all applicable standards of identity, strength, quality, and purity. • To ensure that these standards are met, the FDA requires bioavailability /pharmacokinetic studies and, where necessary, bioequivalence studies for all drug products. • Bioavailability may be considered as one aspect of drug product quality that links in-vivo performance of the drug product used in clinical trials to studies demonstrating evidence of safety and efficacy. • For un-marketed drugs that do not have full NDA approval by the FDA, in-vitro and/or in-vivo bioequivalence studies must be performed on the drug formulation proposed for marketing as a generic drug product. • Furthermore, the essential pharmacokinetics of the active drug ingredient or therapeutic moiety must be characterized. • Essential pharmacokinetic parameters, including the rate and extent of systemic absorption, elimination half-life, and rates of excretion and metabolism, should be established after single- and multiple-dose administration. • Data from these in-vivo bioavailability studies are important to establish recommended dosage regimens and to support drug labeling. 50
  • 53. GM Hamad • In-vivo bioavailability studies are also performed for new formulations of active drug ingredients or therapeutic moieties that have full NDA approval and are approved for marketing. • The purpose of these studies is to determine the bioavailability and to characterize the pharmacokinetics of the new formulation, new dosage form, or new salt or ester relative to a reference formulation. • Clinical studies are useful in determining the safety and efficacy of drug products. • Bioavailability studies are used to define the effect of changes in the physicochemical properties of the drug substance and the effect of the drug product (dosage form) on the pharmacokinetics of the drug. • Bioequivalence studies are used to compare the bioavailability of the same drug (same salt or ester) from various drug products. • Bioavailability and bioequivalence can also be considered as performance measures of the drug product in-vivo. • If the drug products are bioequivalent and therapeutically equivalent, then the clinical efficacy and the safety profile of these drug products are assumed to be similar and may be substituted for each other. TYPES OF BIOAVAILABILIY 1. RELATIVE BIOAVAILABILITY • Relative (apparent) bioavailability is the extent of absorption (as measured by AUC) of a drug as compared to a recognized standard or reference product, both of which given through oral or other route but not through I/V route. A drug the availability of which is compared is called the test formulation. The reference or standard drug is usually with known extent of bioavailability. The relative bioavailability of a drug can be estimated by blood data or by the urine data. • Sometimes the relative bioavailability can be used to compare different conditions as well such as fasting, exercise, etc. RELATIVE BIOAVAILABILITY BY BLOOD DATA • In blood data, relative bioavailability is calculated by the comparing AUC of test and reference drugs. When the test and the reference drug products given at the same dosage level, the relative bioavailability can be obtained for the formula: 51
  • 54. GM Hamad 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐴𝑈𝐶] 𝑇𝑒𝑠𝑡 [𝐴𝑈𝐶] 𝑅𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 • If the above equation is multiplied by 100, it will give percent availability. • When different doses are administered, a correction for the size of the dose is made as given in the formula: 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐴𝑈𝐶] 𝑇𝑒𝑠𝑡 / 𝐷𝑜𝑠𝑒 𝑇𝑒𝑠𝑡 [𝐴𝑈𝐶] 𝑅𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 / 𝐷𝑜𝑠𝑒 𝑅𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 RELATIVE BIOAVAILABILITY BY URINE DATA • Urinary drug excretion data may also be used to measure relative availability whereby the total amount of drug excreted in urine (𝐷 𝑢 ∞ ) after administration of test (T) and reference (R) drugs by using the following formula: 𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐷 𝑢 ∞] 𝑇 [𝐷 𝑢 ∞] 𝑅 • The percent relative availability using urinary excretion data can be obtained by multiplying the above equation with 100. 2. ABSOLUTE AVAILABILITY • Absolute bioavailability is the extent of absorption of a drug after extravascular administration (e.g., oral, rectal, transdermal, subcutaneous) as compared to the extent of the drug availability after administered through I/V route. Thus, absolute bioavailability of drug is measured by comparing the respective AUCs after extravascular and IV administration of a drug. • The absolute bioavailability of a drug using plasma data/ blood data can be measured as follows: 𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐴𝑈𝐶] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂 [𝐴𝑈𝐶]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉 • Absolute availability using urinary drug excretion data can be determined by using the following formula: 𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐴𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = [𝐷 𝑢 ∞] 𝑃𝑂 / 𝐷𝑜𝑠𝑒 𝑃𝑂 [𝐷 𝑢 ∞]𝐼𝑉 / 𝐷𝑜𝑠𝑒𝐼𝑉 52
  • 55. GM Hamad • The absolute bioavailability is also equal to fraction of the dose that is bioavailable, abbreviated as F. When absolute availability is expressed in percent, then F = 1 or 100%. • For drugs given intravascularly or the one which is chemically stable in gastrointestinal tract, such as by IV bolus injection, F = 1 because all of the drug is completely absorbed. • For a drug given through extravascular route or the drugs which undergo first pass effect, the F is always ≤ 1. METHODS FOR ASSESSING BIOAVAILABILITY • Assessment of bioavailability is the estimation of the absorption of drug after its administration. • Methods of bioavailability assessment depends on the assumption that the measurement of the concentration of the drug in a suitable body fluid (usually blood, plasma, urine or occasionally saliva) over period of time after administration can be correlated with the clinical efficacy the drug in treating a given disease condition. • Term bioavailability encompasses the extent of drug absorption and the rate of drug absorption thus, the bioavailability of drug from a drug demands the assessment of the extent and rate of drug absorption of the drug. SIGNIFICANCE OF MEASURING BIOAVAILABILITY • Bioavailability assessment is required for the following situations: - Characterization of the pharmacokinetics of new drug molecules - All new drug formulation - New dosage form of a drug - New dosage strength or dosage regimen - New salt or ester of a drug - New indication of a drug - Administration of drug in special population, e.g., pediatrics - Change in manufacturing process - To determine the safety and efficacy of the drug products - A legal requirement from the drug authorities. 1. BIOAVAILABILITY ASSESSMENT BASED ON BLOOD DATA • Blood data refers to concentration-time data obtained from blood, plasma or serum after administration of drug. The parameters studied in this method are peak plasma (or serum, blood) concentration (Cmax), 53
  • 56. GM Hamad time to reach peak plasma concentration (tmax) and area under the plasma level time curve (AUC). PEAK PLASMA CONCENTRATION (Cmax) • The peak plasma concentration, Cmax represents the maximum concentration of drug in blood plasma following oral administration of a drug. This is usually related to dose and rate constant for absorption and elimination of the drug. • Usually, a relationship exists between pharmacodynamic effect and the plasma drug concentration. • Cmax reflects that a drug is sufficiently absorbed systemically to provide a therapeutic response. • Cmax provides warning of possible toxic levels of drugs. UNITS • The Cmax is measured in terms of concentration, i.e., µg/ml, ng/ml, etc. • Although not a unit for rate, Cmax is often used in bioequivalence studies as a surrogate measure for the rate of drug bioavailability. ESTIMATION OF Cmax • Graphical method - Cmax can be measure directly observing on the plasma level time curve. • Direct method - Direct method for estimation of Cmax involves applying formula: 𝐶 𝑚𝑎𝑥 = 𝐹𝐷0 𝐾𝑎 𝑉𝑑(𝐾𝑎 − 𝐾) (𝑒−𝐾𝑡 𝑚𝑎𝑥 − 𝑒−𝐾𝑎𝑡 𝑚𝑎𝑥) - Where, F = fraction of dose absorbed, D0 = dose of drug, ka = absorption rate constant, k = overall rate constant and tmax is the time for peak plasma concentration. TIME FOR MAXIMUM CONCENTRATION (Tmax) • Time to reach maximum concentration (Cmax), tmax is time required to reach maximum drug concentration after drug administration. At this point, the absorption is maximum, and the rate of drug absorption equals the rate of drug elimination. However, drug absorption continues but at a slower rate after this point. 54
  • 57. GM Hamad • The tmax is a measure of the rate of drug absorption. A lower tmax value represents a faster absorption of drug. Usually, two drugs with same rate (tmax) and extent of absorption (AUC, Cmax), are considered equivalent. • In some special cases, where rate of absorption is different, but the extent is same, the products are considered equivalent. UNITS OF Tmax • The tmax is represented in the units of time, i.e., hours, or minutes. ESTIMATION OF Tmax • Graphical method - Time to reach peak plasma concentration is estimated by direct reading from the plasma concentration versus time profile. • Direct method - Direct method for estimation of Tmax involves applying formula: 𝑡max = 2.303 𝐾𝑎 − 𝐾 log 𝐾𝑎 𝐾 - Where ka is the absorption rate constant, k is the overall rate constant. AREA UNDER THE CURVE (AUC) • Area under the curve (AUC0-∞) is the area under the drug plasma level- time curve from t = 0 to t = ∞ and reflects the total amount of active drug which reaches the systemic circulation following administration of drug. • The drug plasma level-time curve provides the quantitative measurement for bioavailability. The exact shape of plasma concentration profile depends on the relative rates of absorption and elimination and routes of drug administration. Intravenous and sometimes, intramuscular routes yields an early peak due to the fast or almost instantaneous absorption. Whereas oral, subcutaneous, rectal, and other routes demonstrate delayed peaks due to comparatively slower rates of absorption. • The AUC is independent of the route of administration and processes of drug elimination provided the elimination processes do not change. For many drugs, AUC is directly proportion to their dose. In some cases, the 55
  • 58. GM Hamad AUC is not directly proportional to the administered dose for all dosage levels. This is due to the reason that one of the pathways for drug elimination may become saturated. In such case, the AUC increases disproportionally to the increase in dose. The drug pharmacokinetic profile is said to be dose dependent. For the drugs having the dose- dependent kinetics, the bioavailability assessment is difficult. • AUC reflects the following phases: - Absorption phase in which the absorption is greater than elimination. - Distribution phase which is characterized by absorption ≈ elimination. - Elimination phase in which initially absorption rate < elimination rate, then absorption = 0 and at the end, elimination = 0. UNITS OF AUC • AUC is measured in terms of concentration × time, thus, its units are µg.hr/ml, ng.hr/ml or mg.hr/l CALCULATION OF AUC0-∞ • Trapezoidal Rule - Trapezoidal rule involves the breaking up of the plasma concentration vs time profile into various trapezoids (small segments). - Calculating the areas of the individual trapezoids and then added up these areas gives the AUC. 𝐴𝑈𝐶0−𝑡𝑛 = 𝐶 𝑛−1 + 𝐶1 2 (𝑡 𝑛 − 𝑡 𝑛−1) - Where Cn = Concentration of drug under consideration, Cn-1 = concentration of drug in plasma prior to that concentration which is under consideration. While tn and tn-1 are the time of absorption corresponding to Cn and Cn-1, respectively. • Direct method - Under direct method for calculation of AUC0- is use of certain formulae which are as follows: [𝐴𝑈𝐶]0 ∞ = ∫ 𝐶𝑝𝑑𝑡 ∞ 0 56
  • 59. GM Hamad [𝐴𝑈𝐶]0 ∞ = 𝐹𝐷0 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝐹𝐷0 𝐾𝑉𝑑 - Where F = dose absorbed; D0 = dose; k = elimination rate constant; and Vd is the volume of distribution. 2. BIOAVAILABILITY ASSESSMENT BASED ON URINE DATA • Urinary drug excretion data is an indirect method for estimation of the bioavailability. • Bioavailability assessment by urinary data is based upon the assumption that the appearance of drug or its metabolite(s) in urine is the function of the rate and extent of absorption. This assumption, however, is valid only when: - Drug and/or its metabolites is extensively excreted in urine. - Rate of urinary excretion is proportional to the concentration of intact drug in blood plasma. This proportionality does not hold if: ▪ The drug and/or its metabolites is excreted by an active transport process into distal kidney tubules. ▪ The intact drug and/or metabolites is weakly acidic or weakly basic (i.e., there rate of excretion depends upon urinary pH. ▪ The excretion rate depends on rate of urine flow. TOTAL AMOUNT OF DRUG EXCRETED THROUGH URINE (𝑫 𝒖 ∞ ) • Total amount of drug excreted through urine (𝐷 𝑢 ∞ ) is also referred to as the drug ultimately excreted and abbreviated as 𝐴 𝑢 ∞ . The cumulative amount of drug excreted in the urine is proportional to the total amount of drug absorbed. A drug absorbed more; more drug appears in urine. • A cumulative urinary excretion curve is obtained by collecting urine samples at known intervals of time following administration. Enough time is required to collect the entire absorbed drug in urine, which is 5 × t½. • A cumulative urinary excretion curve and the corresponding plasma concentration-time curve obtained after the administration of a single dose of a drug by oral route is given in Figure 1-2. Figure 1 57
  • 60. GM Hamad • This figure reflects the corresponding plasma level time plot and the cumulative urinary drug excretion. The initial A-B reflects the absorption and the slope of this segment of urinary excretion curves is related to the rate of absorption of the drug into blood. • The total amount of intact drug is excreted in urine at point C corresponds to the time at which the plasma concentration of intact drug is zero and essentially all the drug has been eliminated from the body. At this point Du ∞ is obtained. URINARY EXCRETION RATE (dDu/dt) • The elimination follows the first order rate process. The rate of drug excretion depends on the first order elimination rate constant and the drug concentration in plasma. • The plots of plasma level vs time and the rate of urinary excretion rate vs time are similar as depicted in figure which indicates the corresponding plots relating plasma level-time curve and the rate of urinary drug excretion. • The maximum rate of drug excretion would be at point B. While minimum rate of excretion would be at points A and C. TIME FOR COMPLETE EXCRETION (t∞ ) • In the Figure 3-4, the slope of the curve segment AB is related to the rate of drug absorption whereas point C is related to the total time required after drug administration for the drug to be absorbed and completely excreted (t = ∞). • The t∞ is a useful parameter in bioequivalence studies comparing drug products. Figure 2 Figure 3 Figure 4 Figure 4 58
  • 61. GM Hamad 3. BIOAVAILABILITY ASSESSMENT BASED ON THE ACUTE PHARMACODYNAMIC RESPONSE • In some cases, the quantitative measurement of a drug in plasma or urine lacks an assay with sufficient accuracy and/or reproducibility. • For locally acting, non-systemically absorbed drug products, such as topical corticosteroids, plasma drug concentrations may not reflect the bioavailability of the drug at the site of action. • An acute pharmacodynamic effect, such as an effect on forced expiratory volume, FEV1 (inhaled bronchodilators) or skin blanching (topical corticosteroids) can be used as an index of drug bioavailability. • In this case, the acute pharmacodynamic effect is measured over a period of time after administration of the drug product. • Measurements of the pharmacodynamic effect should be made with sufficient frequency to permit a reasonable estimate for a time period at least three times the half-life of the drug. • This approach may be particularly applicable to dosage forms that are not intended to deliver the active moiety to the bloodstream for systemic distribution. • The use of an acute pharmacodynamic effect to determine bioavailability generally requires demonstration of a dose–response curve. • Bioavailability is determined by characterization of the dose–response curve. • For bioequivalence determination, pharmacodynamic parameters including the total area under the acute pharmacodynamic effect–time curve, peak pharmacodynamic effect, and time for peak pharmacodynamic effect are obtained from the pharmacodynamic effect–time curve. • The onset time and duration of the pharmacokinetic effect may also be included in the analysis of the data. • The use of pharmacodynamic endpoints for the determination of bioavailability and bioequivalence is much more variable than the measurement of plasma or urine drug concentrations. 4. BIOAVAILABILITY ASSESSMENT BASED ON RADIOMETRIC METHOD • The radiometric method is based on the radioactivity measurement and involves the administration of radiolabeled drug moiety and determining the total radioactivity in plasma or urine. 59
  • 62. GM Hamad • The estimation of relative availability is based upon the area under the concentration of total radioactivity, apparent drug (or metabolites) in plasma versus time curve. • Sometimes, the estimation under this method is based on the cumulative urinary excretion of total radioactivity. • The method can also reflect the localization of the drug sat several tissue level and pattern of the drug distribution. 5. BIOAVAILABILITY ASSESSMENT BASED ON CLINICAL OBSERVATION • Well-controlled clinical trials in humans establish the safety and effectiveness of drug products and may be used to determine bioavailability. • It is the least accurate, least sensitive, and least reproducible approach • The FDA considers this approach only when analytical methods and pharmacodynamic methods are not available. • Comparative clinical studies have been used to establish bioequivalence for topical antifungal drug products (e.g. ketoconazole) and for topical acne preparations. • For dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be considered acceptable only when analytical methods cannot be developed to permit use of one of the other approaches. 6. BIOAVAILABILITY ASSESSMENT BASED ON IN-VITRO STUDIES • Drug dissolution studies may under certain conditions give an indication of drug bioavailability. • Ideally, the in-vitro drug dissolution rate should correlate with in-vivo drug bioavailability. • Dissolution studies are often performed on several test formulations of the same drug. • The test formulation that demonstrates the most rapid rate of drug dissolution in vitro will generally have the most rapid rate of drug bioavailability in vivo. BIOEQUIVALENCE STUDIES • Difference in preclinical response or adverse event may be due to: - Difference in PK and/or PD behavior of drug. - Difference in bioavailability of drug from drug product. 60