Kinetics class total for student.pdf

Outline
• Introduction
• Drug disposition (distribution and elimination-ADME)
 Kinetics of elimination
• Clearance concept
• Pharmacokinetics models
 One compartment
 IV bolus
 IV infusion
 Extravascular
• Non-compartment PK
• Non-linear PK
• Clinical PK
• Therapeutic drug monitoring
2

Objective
• At the end of this chapter, the student is expected to
 Define the pharmacokinetic processes
 Understand the models used in PK study
 Know how to determine the PK parameters in compartmental
and non-compartmental PK
 Understand the difference between linear and non-linear PK
 Know how to adjust doses and monitor drug level
3

Introduction
• Pharmaco-comes from the Greek word for “drug,” pharmackon,
and kinetics comes from the Greek word for “moving,”
kinetikos.
• Pharmacokinetics (PK) is the study of drug movement into,
around, and out of the body.
 It involves the study of drug absorption, distribution, and
elimination(metabolism and excretion)(ADME)
4

Introduction…
• Application of pharmacokinetic study
 Bioavailability measurements
 Correlation of pharmacological responses with administered doses
 Evaluation of drug interactions
 Effects of physiological and pathological conditions on drug
disposition and absorption
 Dosage adjustment of drugs in disease states, if and when necessary
 Clinical prediction: using pharmacokinetic parameters to
individualize the drug dosing regimen and thus provide the most
effective drug therapy.
5

Introduction…
Pharmacokinetic processes (ADME)
 Absorption
 Absorption is defined as the process by which a drug proceeds
from the site of administration to the site of measurement
(usually blood, plasma or serum)
 Distribution
 Distribution is the process of reversible transfer of drug to and
from the site of measurement (usually blood or plasma)
6

Introduction…
 Any drug that leaves the site of measurement and does
not return has undergone elimination.
 Elimination
 Elimination is the irreversible loss of drug from the site
of measurement (blood, serum, plasma).
 Elimination of drugs occur by one or both of:
 Metabolism
 Excretion.
7

Introduction…
 Metabolism
 Metabolism is the process of a conversion of one
chemical species to another chemical species
 Usually, metabolites will possess little or none of the
activity of the parent drug.
 However, there are exceptions.
 E.g. Procainamide, its metabolite N-acetyl
procainamide is active
8

Introduction…
 Excretion
 Excretion is defined as the irreversible loss of a drug in a chemically
unchanged or unaltered form.
 Disposition
 The processes that occur subsequent to the absorption of the drug.
 Encompasses distribution and elimination phase
9

• Is defined as all the processes that occur subsequent to
the absorption of the drug.
• By definition, the components of the disposition phase are
 distribution and elimination.
10
Drug Disposition

Drug distribution
• Distribution
 Reversible transfer of drug from one location to
another within the body.
 Distribution between blood/plasma, tissues, organ,
body fluids
12

14
Figure: Relative volumes of body fluids into which a drug distributes

Factors affecting drug
distribution
Rate of distribution Membrane permeability
Blood perfusion
Extent of Distribution Lipid Solubility
pH - pKa
Plasma protein binding
Intracellular binding
16

Rate of distribution
• Can be
 Perfusion limited
 Permeability limited
17

Rate of distribution, perfusion
limited
• Perfusion limited
 Drugs that can diffuse rapidly across the capillary endothelium
 Prevails when the tissue membranes present essentially no barrier to
distribution
 The rate of distribution will depend on how quickly drug molecules arrive at
the tissue
18

Rate of distribution, perfusion
limited
 Distribution will depend on perfusion
 Exhibited by low molecular weight lipophilic drugs
 Distribution of drugs dramatically affected if the rate of blood flow to the
tissue is altered
19

Rate of distribution, permeability
limited
• Permeability limited
 Drugs diffusing slowly across the capillary endothelium
 Changes in blood flow will not significantly affect distribution to that tissue
 Permeability limited distribution arises particularly for polar drugs diffusing
across tightly interlocked lipoidal membranes.
20

limited
 Blood-to-brain barrier
 Blood-to-cerebrospinal fluid barrier
• Depends on
 The lipid – water partition coefficient
 Degree of ionization
 Drug's pKa and the pH of the blood
21

limited
• For example, penicillin gets into muscle more quickly than it gets into brain
 Penicillin is quite polar and is thus slowly permeable. Thus transfer of
penicillin is faster in muscle than brain as muscle capillaries are less
restrictive
 Permeability limited transfer
22

Extent of distribution
• Apparent Volume of distribution
 At equilibrium, the extent of distribution is defined by an apparent volume of
distribution (V):
 Apparent Volume of distribution is defined as the volume that would
accommodate all the drugs in the body.
 Expressed as: in Liters
23

Extent of distribution…
24
p
d
C
A
plasma
in
measured
ion
concentrat
body
in the
drug
of
Amount
V 


• A large volume of distribution usually indicates that the drug distributes
extensively into body tissues and fluids.
• Conversely, a small volume of distribution often indicates limited drug
distribution.
• Factors influencing Vd
 Plasma tissue binding ratio
 Warfarin Vs Digoxin
25

 Lipid solubility (lipid : water partition coefficient)
 Streptomycin, Gentamycin Vs benzodiazepines
 Blood flow
 Disease states
26

Extent of distribution…Plasma protein binding
• Many drugs bind reversibly to plasma proteins to form drug–protein
complexes.
• Binding is a function of the affinity of the protein for the drug
• Extensive plasma protein binding will cause more drug to stay in the central
blood compartment
• Drugs which bind strongly to plasma protein tend to have lower volumes of
distribution
27

Extent of distribution…Plasma protein
binding…
• Generally, the higher the lipophilicity of a drug, the greater is its affinity
for plasma proteins.
• Acidic drugs - albumin
E.g. Salicylates, Sulfonamides, Barbiturates, Phenylbutazone, Penicillins,
Tetracyclines, Probenecid
• Basic drugs - 1-acid glycoprotein ,lipoproteins
E.g. Quinine ,Streptomycin, Chloramphenicol, Digitoxin
28

Extent of distribution…Plasma protein
binding…
• Slight changes in the binding of highly bound drugs affects the drug distribution
 Clinical response
 Toxic response
30

Table: Extent of plasma protein binding of selected drugs
31
Extent of distribution…Plasma protein binding…

Elimination
• Elimination is the irreversible loss of drug from the site of measurement.
33

Metabolism of drugs,
Biotransformation
• Chemical alteration of the drug in the body
• Aim: to convert non-polar lipid soluble compounds to polar lipid
insoluble compounds readily excretable products (avoid re-absorption in
renal tubules).
• Most hydrophilic drugs are less bio-transformed and excreted unchanged
– streptomycin.
• The liver is the major site for drug metabolism, but specific drugs may
undergo biotransformation in other tissues, such as the kidney and the
intestines.
35

Biotransformation-Classification
Two Phases of Biotransformation:
Phase I or Non-synthetic
 Metabolite may be active or inactive
 Metabolites are too lipophilic to be retained in the kidney tubules
36

Biotransformation-Classification…
Phase II or Synthetic
 Results in polar, usually more water-soluble compounds that are most often
therapeutically inactive
 glucuronic acid, sulfuric acid, acetic acid, or an amino acid
37

Biotransformation-Classification…
38

Factors that affect the rate of drug
metabolism
• Age
• Liver disease
• Drug interaction
39

Drug excretion
Excretion
The irreversible loss of chemically unchanged drug or intact drug
Renal and non-renal routes of drug excretion
Non-renal routes that a drug can be excreted from the body
Biliary excretion
Breast milk
Lungs:Expired air
Sweat
Saliva
41

First-order elimination or kinetics
• For most drugs, the rate of elimination from the body is proportional
to the amount of drug present in the body (AB).
 Linear pharmacokinetic models
• This type of elimination kinetics is called first-order elimination or
kinetics
• The elimination rate constant (kel) is used to denote how quickly drug
serum concentrations decline in a patient.
43

First-order elimination or kinetics …
• The rate of elimination of the drug that follows first order
elimination can be described as:
 Elimination rate = dA/dt = - k A , where k is the first-
order rate constant.
• With first order elimination,
 Elimination rate is dependent on the concentration of A
present in the body.
 Constant fraction of drug will be removed
44

45
Time after drug
administration
(hrs)
Amount of drug in
body (mg)
Amount of drug
eliminated over
preceding hour
(mg)
Fraction of drug
eliminated over
preceding hour
0 1000 _ _
1 850 150 0.15
2 723 127 0.15
3 614 109 0.15
4 522 92 0.15
5 444 78 0.15
6 377 67 0.15
If 1000 mg of a drug is administered and the drug follows
first-order elimination

First-order elimination or kinetics …
46

Zero-order elimination or kinetics
• If large amount of drug is administered, then order of
elimination process of the drugs will change from a first-
order process to a zero-order process
 Example: Phenytoin, Ethanol , Salicylates
• With zero-order elimination,
 The amount of drug eliminated does not change with AB
 Is called nonlinear pharmacokinetics.
 The fraction removed varies
47

Zero-order elimination or kinetics …
• The rate of elimination of the drug that follows zero order elimination can be
described as:
 Elimination rate = dA/dt = - k*, where k* is the zero-order rate constant
48

49
Time after drug
administration
(hrs)
Amount of drug
in body (mg)
Amount of drug
eliminated over
preceding hour
(mg)
Fraction of drug
eliminated over
preceding hour
0 1000 _ _
1 850 150 0.15
2 700 150 0.18
3 550 150 0.21
4 400 150 0.27
5 250 150 0.38
If 1000 mg of a drug is administered and the drug follows
zero-order elimination

50
Zero-order elimination or kinetics
…

Clearance
• Clearance is a more useful concept in measuring drug
elimination than kel since it takes into account blood flow
rate.
• The Clearance (Cl) of a drug is defined as the volume of a
biological fluid (generally plasma) from which that drug is
removed ("cleared") in the unit of time (min).
• Expresses the ability of kidney and liver to remove drug
from the systemic circulation.
52

Clearance…
• NB:
 Clearance doesn’t indicate the amount of drug being removed,
 it indicates the volume of plasma(blood) from which the drug is removed or cleared, in a
given time period.
• Clearance is the constant of proportionality between the rate of drug
elimination and the plasma concentration.
 Rate of elimination = Cl X Cp
53

Clearance…
 For first order elimination, Rate of elimination = Kel X Amount in body
 Kel X Amount in body = Cl X Cp
 Therefore, Cl= Kel X Vd
 Drugs can be cleared from the body by many different mechanisms, pathways,
or organs, including hepatic biotransformation and renal and biliary excretion.
54

Clearance…
55
Renal clearance = rate of elimination by kidney
C
Hepatic clearance = rate of elimination by liver
C
Other organ clearance = rate of elimination by organ
C
 CL total = CL renal + CL hepatic + CL pulmonary +CL others

Clearance…
Physiologic/Organ Clearance
• Many organs in the body have the capacity for drug elimination
• The kidneys and liver are the most common organs involved in excretion and
metabolism, respectively
56

Clearance…
 Let’s consider a single organ, kidneys and Q (mL/minute) which is blood flow
through the organ, Cin , the drug Conc. in the blood entering the organ and Cout ,
the drug Conc. in the exiting blood.
 Clearance is dependent on the blood flow to the organ (Q) and on the ability of
the organ to extract the drug from the blood stream and eliminate it (E)
57

Clearance…
• The organ’s ability to remove a drug can be measured by
relating Cin and Cout. This is called Extraction ratio
• If Cout = 0, the drug will be totally removed and the E will be
1.
• If Cout = Cin, there is no drug removal and the E will be 0.
59
in
out
in
C
C
C
E



Clearance…
• Generally, “E” lies somewhere between 0 and 1
• Organs that are very efficient at eliminating a drug will
have an extraction ratio approaching one.
• Therefore , the drug clearance of any organ is determined
by blood flow and the extraction ratio:
 Organ Clearance = Blood flow X extraction ratio
Clorg = Q*E
60

Introduction
• The handling of a drug by the body can be very complex, as
several processes (such as ADME) work to alter drug
concentrations in tissues and fluids.
• Simplifications of body processes are necessary to predict
a drug's behavior in the body.
 Application of mathematical principles to the various
processes
 A model of the body must be selected
62

Introduction…
• Pharmacokinetic models are divided into
 Compartment model
 Physiologic model (flow model)
 Non-compartmental model
• The most useful model is the compartment model.
63

Compartment model
• The living system is conceived to be composed of a number
of mathematically interconnected compartments.
• A compartment is a group of tissues which behaves
uniformly with respect to the drug movement.
• The compartments do not represent a specific tissue or fluid
but may represent a group of similar tissues or fluids.
 Organs and tissues in which drug distribution is similar
are grouped into one compartment.
64

Compartment model…
• For example, distribution into muscle and adipose tissue differs from
distribution into renal tissue for most drugs.
• The highly perfused organs (e.g., heart, liver, and kidneys) often have similar
drug distribution patterns, so these areas may be considered as one
compartment.
65

• There are three types of compartment models in pharmacokinetics:
 One-compartment model
 Two-compartment model
 Multicompartment model
66

• One compartment model
 The body is viewed as a single compartment
 All the tissues where a drug goes have a very rapid rates of drug uptake
 Instantaneous distribution
 Two compartment model
 The body is viewed as two compartments
67

 The central compartments
 The peripheral compartments
 Central compartment consists of the plasma and tissues
that take up the drug so rapidly that distribution can be
considered to be instantaneous.
 Peripheral compartment consists of tissues that take up
the drug at slower rate than tissues in the central
compartment
68

• Three compartment model
 An extension of the two compartment model, where a sizable amount of the
drug distributes to certain very poorly perfused tissues, such as fat and
bone, at an extremely slow rate.
 The three compartment model has three group of tissues:
69

 Central compartment tissues: take up the drug very rapidly
 Peripheral tissues: compartment take the drug more slowly
 Deep tissue compartment: take the drug at an extremely
slow rate
70

One compartment model
• It is the most frequently used model in clinical practice.
• Following drug administration, the body is depicted as a kinetically
homogeneous unit
73

One compartment model…
• Intravenous bolus administration
• Continuous infusion
• Extravascular administration
• Multiple dosage regimens (home study)
74

75
Intravenous bolus administration

Intravenous bolus Administration
• Drug is injected all at once into a box, or compartment,
• The drug distributes instantaneously and homogenously throughout the
compartment.
• Drug elimination also occurs from the compartment in first order fashion.
76
1
kel

Intravenous bolus…
• Consider a single IV bolus injection of drug X.
 As time proceeds, the amount of drug in the body is:
dCp/dt = rate-in (availability) – rate out (elimination)
• Since rate-in or absorption is absent, the equation becomes
dCp/dt = - rate out
• If rate out or elimination follows first order kinetic
78

79
p
el
p
C
.
k
dt
dC


Integrating this formula gives
t
k
0
t
el
e
Cp
Cp 


 Where,
 Cpt is the concentration at any time t
 Cp
0 is the concentration at time 0
 kel is the elimination rate constant
80

• Example: If we know that the plasma drug concentration just after a gentamicin dose is 8 mg/L and
the patient's elimination rate constant is 0.25 hr-1, calculate the concentration 8 hours later?
• Given:
 Co = 8 mg/L
 Kel = 0.25 h-1
 t = 8 hr
• Reuired :
 Ct8 = ?
solution:
C = C0e-Kt
Cat 8 hr = 8 mg/L X e-0.25 hr-1(8 hr) = 8 mg/L (0.135) = 1.1 mg/L
81

• NB:
 The term e-Kt indicates the fraction of the initial dose of drug that
remains in the body at time t;
 0.135 (or 13.5%) remains in the body 8 hours after the initial dose in this example.
 Conversely, the term 1 - e-Kt would indicate the percent or fraction
excreted after time (t).
82

• The above equation describes the single exponential
decline in drug concentration as a function of time.
• This fall in plasma concentration is called mono-
exponential decay.
• If we know kel and Cp0, we could calculate Cp at any time
after a single IV bolus dose.
• However, it still isn't very convenient for estimating a value
of kel from concentration versus time data.
83

• For estimation purposes, it is preferable to use a straight line equation.
• A straight line equation can be achieved by taking the natural logarithm of both
side of Equation
84
t
k
Cp
ln
Cp
ln el
0
t 

2.303
t
k
Cp
log
Cp
log el
0
t 


• Hence, Plotting ln(Cp) versus t should give a straight line with a slope of - kel and
an intercept of ln(Cp0) (y = mX + b with b = intercept and m = slope)
85

86
 C0 can be determined
from a direct
measurement or
estimated by back-
extrapolation
 K is the slope
 C0 can be determined
from a direct
measurement or
estimated by back-
extrapolation
 K is the slope

Elimination rate constant
• Elimination rate constant (k) represents the fraction of drug removed per unit of
time and has units of reciprocal time (e.g., minute-1, hour-1, and day-1).
87
 
2
1
2
1 ln
ln
t
t
C
C
kel



• where t1 and C1 are
the first
time/concentration
pair and t2 and C2
are the second
time/concentration

Half life
• It is the time required for the concentration of drug in the plasma to decrease
by half.
• Consider: ln C = ln C0-Kt
• By definition, at one half-life, the concentration (C) at the time (t) is half of what
it was initially (C0).
• So we can say that at t = t1/2, C = 1/2C0.
88

Half life…
• Example: If a dose of gentamicin is administered and a peak plasma
concentration is 6 mg/L after the infusion is completed and is 1.5 mg/L 4 hours
later, calculate half life of the drug?
89
2
1
el
0
0
t
k
Cp
ln
Cp
2
1
ln 

el
el
o
o
el
o
o
1/2
k
ln2
k
/C
ln2C
k
1/2C
C
ln
t 


el
k
0.693


Half life…
 Solution:
 First the elimination rate constant (Kel) is calculated as shown previously, then Half-life can
be calculated from k.
90
348
.
0
4
39
.
1
4
0
/
6
ln
5
.
1
ln
ln
ln 1
1
0
1 










 hr
hr
L
mg
t
t
C
C
k o
el
hr
kel
2
693
.
0
t1/2 

Then,
 Given: Co = 6mg/L
C1 = 1.5mg/L
t1 = 4 hr
− Required: t1/2 = ?

Quiz
• Exercise: A patient was given an intravenous loading dose of Phenobarbital 600
mg. One day and four days after the dose was administered, phenobarbital
serum concentrations were 12.6 mg/L and 7.5 mg/L, respectively. Compute Kel,
t1/2, Vd and C0
91

Apparent volume of distribution
• Vd is the constant of proportionality that relates the total amount of drug in the
body at any time to the corresponding plasma concentration.
 Immediately after the IV dose is administered the AB, is the IV dose
92
p
B
d
C
A
plasma
in
measured
ion
concentrat
body
in the
drug
of
Amount
V 


Apparent volume of distribution…
 At this time, elimination is not yet started
 It has an insignificant effect on the administered dose
 Combining the above Equation and Equation for IV
bolus, C = C0e-Kt , we are able to derive an equation for
drug concentration as a function of time given values of
Dose, Vd, and kel.
93
o
p
d
C
Dose
v 
d
o
p
v
Dose
C 

• Calculation of kel and half-life may be determined from CL and Vd.
94
t
k
d
p
el
e
.
V
Dose
C 

CL
V
0.693
k
0.693
t
V
CL
k d
el
2
1
d
el 




• Example: A patient is given a theophylline loading dose of 400 mg intravenously.
Because the patient received theophylline during previous hospitalizations, it is
known that the volume of distribution is 30 L, the elimination rate constant
equals 0.116 h−1. Compute the expected theophylline concentration 4 hours
after the dose was given?
95

• Given
 D (Dose) = 400 mg
 Vd = 30 L
 Kel = 0.116h-1
 t = 4 hr
• Required
 Ct = ?
• Solution: a one-compartment model intravenous bolus equation can be used:
 C = (D/V)e−kelt = (400 mg/30 L)e−(0.116 h−1)(4 h) = 8.4 mg/L.
96

• Example: A patient is given an IV dose of vancomycin 1000 mg. Since the patient
has received this drug before, it is known that the Vd equals 50 L, the
elimination rate constant is 0.077 h-1. Calculate the expected vancomycin
concentration 12 hours after the dose was given?
97

• Solution: A one compartment model IV bolus equation can
be used:
C = (D/V)e-kelt = (1000 mg / 50 L)e-(0.077 h-1)(12 h) = 7.9 mg/L.
98

Clearance
• Total body clearance is an important pharmacokinetic parameter that is often
defined as the volume of blood or plasma completely cleared of the drug per
time.
• It is also the proportionality constant relating the rate of elimination and drug
concentration.
99
p
el
p
el
p
p
C
A
.
k
C
A)
k
_(
C
dt
dA
CL
C
.
CL
dt
dA







 d
el V
k


Clearance…
• Clearance can also be calculated using the integral of Equation
100
p
C
dt
dA
CL


AUC
Dose
dt
C
dt
dt
dA
C
dt
dA
CL
p
p







Area under the plasma concentration
time curve (AUC)
• AUC: reflects the actual body exposure to drug after administration of a dose of
the drug and is expressed in mg X h/L.
• This area under the curve is dependent on
 The rate of elimination of the drug from the body
 The dose administered
AUC =
S∗F∗Dose
Clearance
=
SFD
Cl
=
D
Cl
101

Area under the plasma concentration
time curve (AUC)
• Fractional bioavailability (F)
 F is the fraction of an oral dose that reaches the systemic circulation,
which following oral administration may be less than 100%.
 Thus, if F = 0.5 then 50% of the drug is absorbed.
 Parenteral dosage forms (IM and IV) assume a bioavailability of 100%, and so
F = 1; it is therefore not considered and is omitted from calculations.
• Salt factor (S)
 S is the fraction of the administered dose, which may be in the form of
an ester or salt, that is the active drug.
 Eg. Aminophylline is the ethylenediamine salt of theophylline, and S is
0.79.
 Thus 1 g aminophylline is equivalent to 790 mg theophylline.
102

Calculation of AUC using the
Trapezoidal Rule
• AUC can be calculated directly from the Cp versus time data.
• can be determined by the application of trapezoidal rule and can be
obtained by using an equation
( ) ∗=
∗
103

Calculation of AUC…
• Trapezoidal rule is the simplest and most common approach of calculating AUC.
• We can calculate the AUC of each segment if we consider the segments to be
trapezoids [Four sided figure with two parallel sides].
104

• The area of each segment can be calculated by multiplying the average
concentration by the segment width.
• For example, for the segment from Cp1 to Cp3, the AUC will be:
• AUC = ∑ ( − ) + ( − )
106

• If we assume that the last data points follow a single exponential decline (a
straight line on semi-log graph paper) the final segment can be calculated from
the equation above from tlast to infinity:
107

• Thus, the total AUC can be calculated as:
108

• Example:
 An 80-mg dose of drug Y is administered as an intravenous bolus, and the
following plasma concentrations result. Calculate the area under the curve
(Kel = 0.239 h-1).
109

Exercise
 A 250 mg dose of a drug was administered intravenously to 60 yr. 80 kg male
subject. The blood concentration time data is presented in table below. Calculate
the AUC, clearance and Volume of distribution? (First order kinetics)
111

Continuous intravenous infusion
• Most drugs given intravenously cannot be given as an actual
intravenous bolus because
 Side effects related to rapid injection.
 For instance, vancomycin IV bolus: hypotension and
red flushing around the head and neck areas
 Unsuitable when it is necessary to maintain plasma or
tissue concentrations at a concentration that will prolong
the duration of drug effect.
113

114
 F
Figure: A representation of the plasma concentration (Cp) versus time
profile following the administration of a single intravenous (IV) bolus
dose. MTC, minimum toxic concentration; MEC, minimum effective
concentration.

Continuous intravenous…
• Therefore, it may be given by slower IV infusion over 15 or
30 minutes or more.
• If a drug is chemically stable and compatible with the IV
fluid, it may be added to the fluid and thereby be given by
slow infusion.
• The pharmacokinetics of a drug given by constant IV
infusion follows a zero-order input process in which the
drug is infused directly into the systemic blood circulation.
115

• Therefore, the infused drug follows zero-order input and first-order output.
• k0 represents infusion rate which is a zero order process so the units of k0 are
amount per time, for example 25 mg/min.
116

• The change in the amount of drug in the body at any time (dAB/dt)
during the infusion is the rate of input minus the rate of output. The
differential equation for V • Cp is then:
• After dividing both sides by the apparent volume of distribution, V or
substituting A with V X Cp
117
A
.
k
k
dt
dA
el
o 
  
t
k
- el
e
-
1
.
el
o
k
k
A 
 
t
.
k
-
d
el
o
t
el
e
-
1
.
V
.
k
k
Cp 

• Example: A drug (Cl= 2L/h, Vd= 50 L) is administered as an
intravenous infusion at a rate of 10 mg/h. Calculate the plasma
concentration after 4 h of infusion.
 Solution: Ko = 10mg/h, Cl= 2 L/h, Vd = 50 L, kel = Cl/Vd= 2/50= 0.04
h−1
118
 
t
.
k
-
d
el
o
t
el
e
-
1
.
V
.
k
k
Cp 

Steady-state drug concentration
Steady-State Drug Concentration (CpSS)
• When an IV infusion is started at a constant rate in one-
compartment model, there is no drug present initially, so
plasma concentration (C) is zero.
• As the infusion continues, Cp increases, initially quickly, but
then more slowly,
 rate of elimination << rate of infusion
• If we continue the infusion indefinitely,
 rate of infusion = rate of elimination
119

Steady-state drug concentration…
 Steady state plasma concentration
 In other words, there is no net change in the amount of drug in the body, AB, as
a function of time during steady state.
120

121

• We can determine the steady state concentration from the differential equation
by setting the rate of change of Cp, i.e. dCp/dt = dA/dt = 0.
• This could also be calculated from the integrated equation by setting e- kel • t = 0
at t = ∞.
122





 ss
p
d
el
o
ss
p
d
el
o C
.
.V
k
k
C
.
V
.
k
k
0
dt
dA
 
t
.
k
-
d
el
o
t
el
e
-
1
.
V
.
k
k
Cp 
CL
k
V
.
k
k
C o
d
el
o
ss
p 

 
d
el
o
.
k
-
d
el
o
p
V
.
k
k
e
-
1
.
V
.
k
k
C el

 
ss

• Since the apparent volume of distribution, elimination rate
constant, and elimination half life (t1/2) are constants for a
given drug administered to a particular patient
 The absolute value of steady-state plasma concentration
is determined only by the rate of infusion
 For instance, if the rate of infusion is increased by a
factor of two, the steady-state plasma concentration will
also increase by a factor of two.
123
d
el
o
ss
p
V
.
k
k
C 

• Example1: An antibiotic has a volume of distribution of 10 L and a kel of 0.2 hr– 1. A steady-state
plasma concentration of 10 μg/mL is desired. Calculate the infusion rate needed to maintain this
concentration?
• Given :
 Vd = 10L
 Kel = 0.2hr-1
 Cpss = 10 ug/mL
• Required :
 Ko = ?
• Solution:
124
     mg/hr
20
0.2
ml
1000
ml
10
μg/ml
10
k
.
V
.
C
k
hr
-
el
d
ss
p
o



d
el
o
ss
p
V
.
k
k
C 

 Example2: A desired steady state plasma concentration of theophylline may be 15
mg/L. The average half-life of theophylline is about 4 hr and the apparent volume of
distribution is about 25 liter. What infusion rate is necessary?
• Given:
 Cpss = 15 mg/L,
 t1/2 = 4 hr,
 Vd = 25L
• Required
 Ko = ?
125

Solution:
First calculate kel from the t1/2,
o kel = 0.693/4 = 0.17 hr-1,
Then
o k0 = kel • Vd • Cp = 0.17 x 25 x 15 = 63.8 mg/hr.
126

Time to reach steady state
• In Clinical practice, the activity of the drug will be observed when the drug
concentration is close to the desired plasma drug concentration, which is usually
the target or desired steady-state drug concentration.
• Mathematically, the time to reach true steady-state drug concentration, C SS, would
take an infinite time.
• The time to reach 90%, 95%, and 99% of the steady-state drug concentration, Css,
may be calculated.
127

Time to reach steady state…
• For therapeutic purposes, the time for the plasma drug concentration to reach
more than 95% of the steady-state drug concentration in the plasma is often
estimated.
128

• Example: How many half-lives does it take to get to 95% steady state?
 Solution: At 95% of steady state, Cpt = 0.95Cpss. Let kel = 0.693/t1/2. substituting
into previous equation for Cpt and kel gives us
=
∗
1 − ∗ / =
∗
129

• NB:
 The steady-state concentration (C SS) is dependent on the volume of distribution, the
elimination rate constant, and the infusion rate.
 For a drug with one-compartment characteristics, the time to reach steady state is
independent of the dose, the number of doses administered, and the dosing interval,
but it is directly proportional to the half-life.
130
• Exercise:
 How many half-lives does it take to get to 99% steady state?

• Solution : The time to reach steady state can be calculated in terms of t1/2 as
follows.
131
d
V
el
o
ss
p
k
k
C  99% steady-state level,
d
0
0
V
99
el
o
k
k
 Substituting into intravenous infusion Equation for C p, we can
find the time needed to reach steady state by solving for t.
    t
k
t
k
-
d
el
o
d
el
o
t
.
k
-
d
el
o
p
el
el
el
e
1
99
.
0
e
-
1
.
V
k
k
V
k
k
99
.
0
e
-
1
.
V
.
k
k
C 







• Substituting (0.693/t 1/2) for
132
el
el
el
ss
99
el
k
4.61
k
4.61
k
0.01
ln
t
0.01
ln
t
k 0
0 








1/2
ss
99
1/2
1/2
ss
99 6.65t
t
t
0.693
4.61
t
0.693
4.61
t 0
0
0
0 




133
Table: Number of t1/2 to reach a fraction of CSS

134
• Example : A patient was given an antibiotic (t 1/2 = 6 hr) by constant IV infusion at a rate
of 2 mg/hr. At the end of 2 days, the serum drug concentration was 10 mg/L. Calculate
the total body clearance Cl T for this antibiotic?
• Given
 t1/2 = 6 hr
 Ko = 2 mg/hr
 t = 2 days = 48 hr
 Cp48h = 10 mg/L
• Required
 ClT =?
• Solution
 
 
 
  hr
ml
hr
L
e
hr
t
k
and
e
C
k
Cl el
t
k
pt
o el
/
200
/
2
.
0
)
0039
.
0
1
(
*
2
.
0
1
10
2
1155
.
0
6
693
.
0
693
.
0
,
1
e
-
1
.
Cl
k
Cp
e
-
1
.
V
.
k
k
Cp
48
*
1155
.
0
1
2
/
1
t
.
k
-
o
t
t
.
k
-
d
el
o
t
el
el

















• Or
 The serum sample was taken after 2 days or 48 hours of infusion, which time represents 8 x
t 1/2, therefore, this serum drug concentration approximates the CSS.
135
ml/hr
200
mg/L
10
mg/hr
2
C
k
CL ss
p
0
T 



Loading and maintenance dose
• One reason we give a drug by IV is because we need a
quick therapeutic response.
• One way to achieve a therapeutic concentration more
quickly is to give a loading dose by rapid intravenous
injection and then start the slower maintenance infusion.
• If the volume of distribution and elimination rate
constant can be estimated for a patient, a loading dose
and initial maintenance dose can be computed.
136

Loading dose
• The loading dose can simply be calculated from the product of
target concentration and volume of distribution VD.
• If the target concentration is steady state concentration for a
continuous intravenous infusion dosage regimen, DL is
computed using the following equation:
137



el
o
d
el
ss
p
o
k
k
V
.
k
.
C
k L
d
ss
p D
V
.
C 

Loading dose
• NB:
 Knowledge of volume of distribution allows calculation of
the drug dose required to achieve a target concentration
138

Maintenance dose
• To maintain a target steady state Cp
ss, the drug must be
administered at a rate equal to the rate of elimination at
that concentration i.e.
 rate of administration = rate of elimination.
• Since rate of elimination = CL x Cp
ss; and rate of
administration = ko
• Maintenance dose rate (mg / h) = Target Css (mg / L) x CL
(L / h)
139

Maintenance dose…
 Knowledge of clearance allows calculation of the dose rate required to maintain
a target steady state concentration (Cp
ss).
• This means that if the dose is altered, the steady state concentration will change
in direct proportion to the change in dose.
140

• Example: A patient with a ventricular arrhythmia after a myocardial infarction
needing treatment with lidocaine at a Cp
ss of 3.0 mg/L (population
pharmacokinetic parameters used: Vd = 50 L, Cl = 1.0 L/min). Calculate the
loading and maintenance dose?
• Given
 Cpss = 3.0 mg/L
 Vd = 50L
 Cl = 1.0 L/min
• Required
 DL = ?
 DM = ?
141
Loading and maintenance dose

Loading and maintenance dose…
• Solution:
 LD = Cpss * Vd = (3 mg/L)(50 L) = 150 mg
 k0 = Cpss * Cl = (3 mg/L)(1.0 L/min) = 3 mg/min.
 The patient would be prescribed lidocaine 150 mg intravenously followed by a 3
mg/min continuous infusion.
142

• Example: Calculate gentamicin dose required to achieve a peak
gentamicin concentration of 10 mg/l in a neonate weighing 1 kg
and Vd of 0.5 litre/kg ?
• Solution:
 Loading dose = target concentration X Vd = 10 mg/l × 0.5
liter/kg × 1 kg = 5mg.
143
Loading and maintenance dose…

144
Extravascular administration

Extravascular… Introduction
• Extravascular drug administration refers
 any route of drug administration where the drug is not administered directly
into the systemic circulation.
• Thus, access of the drug to the systemic circulation, or absorption, is a
critical pharmacokinetic characteristic of extravascular administration.
145
Fig: Typical plasma concentration–time profile after extravascular drug administration.

Introduction…
• Immediately after drug administration (area A), Cp increases
because the rate of absorption(Ra) is greater than the rate of
elimination(Re).
 The amount of drug in the GIT is at its maximum, so the Ra is
also maximum. In contrast, initially the amount of drug in the
body is small, so the Re is low.
• As the absorption process continues, drug is depleted from the
GIT, so the Ra decreases.
• At the same time, the amount of drug in the body increases, so
the Re increases.
 At the peak (B), the Ra is momentarily equal to the Re.
146

Introduction…
• After this time, the rate of elimination exceeds the rate of absorption and
plasma concentrations fall (area C).
• Eventually, all the drug is depleted from the intestinal tract and drug absorption
stops.
 At this time (area D) the plasma concentration is influenced only by
elimination.
147

Model for first-order absorption in a one-
compartment model
• The absorption of drugs from the gastrointestinal tract
often follows first-order kinetics.
• As a result, the pharmacokinetic model can be created
simply by adding first-order absorption into the central
compartment of the one-compartment model
• This model can be represented as:
148

Model for first-order absorption…
149
 Where
 Xg is the amount of drug to be absorbed
 Xp is the amount of drug in the body
 ka is the first order absorption rate constant
 kel is first order elimination rate constants

• The amount of drug in the body at any time will depend on
the relative rates of drug in(absorption) and out
(elimination):
• Rearranging and integrating the above equation yields:
150
el
p
g
a
p
k
.
X
X
.
k
dt
dX



• where
 (Xp)t is the mass (amount) of drug in the body at time t;
 Xg0(Dose) is the mass of drug at the site of administration
(the administered dose);
 F is the fraction of drug absorbed;
 (Xg)t=o = FXg0 and is the mass of administered dose that is
available to reach the general circulation
151
 
 
   





 

 t
k
t
k
-
el
a
0
g
a
t
k
t
k
-
el
a
0
t
g
a
t
P
a
el
a
el
e
e
k
k
FX
k
e
e
k
k
X
k
X  
t
k
t
k
-
el
a
a a
el
e
e
k
k
Dose
F
k 



• The above Equation can be written in concentration (Cp) terms
by substituting Cp X Vd for Xp:
Where
 KaFXg0/Vd (Ka – Kel) is the intercept of the plasma drug
concentration versus time plot.
152
 
 
 
t
k
-
t
k
-
el
a
d
0
g
a
t
p
a
el
e
e
k
k
V
FX
k
C 



Absorption rate constant …
• After EV drug administration, the plasma concentration at any
given time is given by:
• If we denote KaFXg0/Vd (Ka – Kel) as A
• when Ka > Kel, approaches zero, and the extrapolated line
is given by:
153
 
 
 
t
k
-
t
k
-
el
a
d
0
g
a
t
p
a
el
e
e
k
k
V
FX
k
C 


  t
-k
t
k
t
P
a
el
e
A
e
A
C 
 
t
-k a
e
t
kel
e
A
C' 


• Subtracting Cp from C’ we get
• Taking natural logs
154
 
 
t
k
-
el
a
d
0
g
a
diff
a
e
k
k
V
FX
k
Cp
or
Cp
-
C'


 
 
t
.
k
-
k
k
V
FX
k
Cp
C'
ln a
el
a
d
0
g
a



  t
.
k
-
A'
Cp
C'
ln a



• A plot of this difference between extrapolated and observed
Cp against time, on semi-logarithmic paper should yield a
straight line, which, in turn, should allow determination of:
 The first-order absorption rate constants, Ka= - Slope
 Absorption half life , t1/2= 0.693/Ka
155

156

Apparent volume of distribution
• For a drug administered EV route of administration, the Vd
can be calculated from Cp data in two ways.
 If F (the fraction of administered dose that reaches
the general circulation) is known:
 If F is not known, the ratio of V/F will be calculated as
follow:
157
 
el
a
d
a
k
k
V
FDose
k
Intercept


  









Intercept
1
k
k
Dose
k
F
V
el
a
a
d

Peak time (tmax)
• Mathematical relationships can be developed to estimate the time at which
a peak plasma concentration of drug should be observed and the maximum
plasma concentration at this time following first-order input into the body.
• Expanding Eqn. yields,
• which when differentiated with respect to time gives
• When the plasma concentration reaches a maximum (Cmax) at time tmax,
dC/dt = 0. Therefore,
158
   
t
a
k
-
e
el
k
a
k
d
V
0
g
FX
a
k
t
el
k
-
e
el
k
a
k
d
V
0
g
FX
a
k
t
p
C










   
t
el
k
-
e
el
k
a
k
d
V
0
g
FX
el
k
a
k
t
a
k
-
e
el
k
a
k
d
V
0
g
FX
k2



 a
dt
dC
  














 t
a
k
-
e
-
t
el
k
-
e
el
k
a
k
d
V
0
g
FX
a
k
t
p
C
   
max
t
el
k
-
e
el
k
a
k
d
V
0
g
FX
el
k
a
k
max
t
a
k
-
e
el
k
a
k
d
V
0
g
FX
k2



a

Peak time (tmax)
• Which reduces to
• Taking the natural logarithm of both sides of the Eqn. and solving for tmax
yields
• For a given drug, as the absorption rate constant increases, the time
required for the maximum plasma concentration to be reached decreases.
max
t
a
k
-
max
elt
-k
el
k
a
k
e
e

el
k
a
k
el
k
a
k
ln
max
t










159

Maximum [peak] plasma concentration
[Cp] max
• There are two methods available for determining peak
plasma concentration (Cp) max.
• Method 1: Peak plasma concentration obtained from the
graph of plasma concentration versus time.
160

Maximum [peak] plasma…
• Method 2: Peak plasma concentration obtained by substituting
t with tmax in the original extravascular equation.
 As the ka value is becoming smaller, the Cp max gets lower
and the onset becomes slower.
 Thus the higher the F value the higher the concentration
values at each time point.
161
 
 
   
 
 
max
a
max
el
a
el t
k
t
k
el
a
d
o
g
a
max
p
t
k
-
t
k
-
el
a
d
0
g
a
t
p e
e
k
k
V
FX
k
C
e
e
k
k
V
FX
k
C 









162
Non-compartment pharmacokinetics

Introduction
• Non compartmental methods used to determine certain
pharmacokinetic parameters without deciding on a particular
compartmental model.
• Non compartmental method offers several benefits over
compartmental analysis:
 Fewer plasma samples may be required than in multicompartmental
analysis.
 The timing of the samples is not as critical as it is for
multicompartmental analysis.
163

 The modeling process is more straightforward and
requires less experience and skill on the part of the
modeler.
 It avoids a problem frequently encountered with the
compartmental approach, where a drug displays one-
compartmental properties in some subjects, and multi
(two or even three)-compartmental properties in other
participants.
164
Introduction…

• After an intravenous bolus drug dose (D0), the drug molecules
distribute throughout the body.
• These molecules stay (reside) in the body for various time
periods.
• Some drug molecules leave the body almost immediately
after entering, whereas other drug molecules leave the body
at later time periods.
 The term mean residence time (MRT) describes the average
time for all the drug molecules to reside in the body.
165
Mean residence time(MRT)

MRT= Total residence time for all drug in the body
Total number of drug molecules
 The basic calculations are based on the area
under the plasma concentration versus times
curve (AUC) and the first moment curve
(AUMC)(the area under the curve of the plot of Cp·t versus
time from zero to infinity).
166
Mean residence time(MRT)…

167

168

169

Determination of other important
pharmacokinetic parameters
 The elimination rate constant
 =
 The elimination half-life
 / =
.
 The clearance
 =
 Volume of distribution
 = ∗ =
∗
170
 The other important pharmacokinetic parameters, including the mean elimination
rate constant, the mean elimination half-life, the volume of distribution at steady
state, and clearance can be determined as follows.

Mean Absorption Time (MAT)
• After IV bolus injection, the rate of systemic drug absorption is
zero.
 The MRT calculated for a drug after IV bolus injection basically reflects
the elimination rate processes in the body (MRT = 1/k).
• After oral drug administration, the MRT is the result of both drug
absorption and elimination.
 The relationship between the mean absorption time, MAT, and MRT is
given by
MRTOral = MAT + MRTIV
MAT = MRTOral - MRTIV
171

Other parameters…
 MAT,
 ka’
 F:
 Clearance
172

Other parameters…
• Example:
 Dose = 50 mg
 K = 0.2 h-1
173

Other parameters…
176
= =
.
= . L/h
Vd = Cl ∗ MRT =3.96*4.92 = 19.48L
 Determination of Clearance
 Determination of volume of distribution

178
Non-linear pharmacokinetics

Introduction
• Previously, linear pharmacokinetic models using simple first-order
kinetics were introduced to describe the course of drug ADME.
• These linear models assume that the pharmacokinetic parameters
for a drug would not change when different doses or multiple doses
of a drug are given.
179

Introduction…
• With some drugs, increased doses can cause deviations from the linear
pharmacokinetic profile previously observed with single low doses of the same
drug.
• This nonlinear pharmacokinetic behavior is termed dose-dependent
pharmacokinetics
• Most of the times, the reason for non-linearity is the saturation of a particular
process involved in drug absorption, distribution, metabolism or elimination.
180

Introduction…
• Drugs that demonstrate saturation kinetics usually show the
following characteristics.
1. Elimination of drug does not follow simple first-order kinetics—that is,
elimination kinetics are non-linear.
2. The elimination half-life changes (increases) as dose is increased due to
saturation of an enzyme system.
3. The area under the curve (AUC) is not proportional to the amount of
bioavailable drug.
181

3. The saturation of capacity-limited processes may be affected by other drugs
that require the same enzyme or carrier-mediated system (i.e., competition
effects).
4. The composition and/or ratio of the metabolites of a drug may be affected
by a change in the dose.
182

183
III. Clinical Pharmacokinetics

Introduction
 Clinical pharmacokinetics: is the process of applying
pharmacokinetic principles to determine the dosage
regimens of specific drug products for specific patients
Clinical pharmacokinetics enables drug regimens to be
tailored for individual patients, while minimizing treatment
failures and adverse effects
To the safe and effective therapeutic management of
drugs in an individual patient
184

Dosage regimen adjustment in renal
impairment
• Most water-soluble drugs are eliminated unchanged to some extent by the
kidney.
• Drug metabolites that were made more water soluble via oxidation or
conjugation are typically removed by renal elimination.
Normal kidney function is very important for drug elimination from the body.
185

impairment…
• Overall, kidney function evaluated by Glomerular Filtration Rate (GFR)
• The most convenient method to estimate the GFR is by calculating creatinine
clearance (CrCl)
 Creatinine is a by-product of muscle metabolism that is primarily eliminated
by glomerular filtration.
186

impairment…
• Cockcroft and Gault equation
 Adults aged 18 years and older
 Actual weight within 30% of their ideal body weight (IBW)
 IBWmales(In Kg)=50 + 2.3 (Ht-60)
 IBWfemales (in Kg)= 45 + 2.3 (Ht-60), Ht is height in inches
 Stable serum creatinine concentrations
 For males,
187
 
 
cr
est
S
BW
age
CrCl



72
140

impairment…
 For females,
 Where CrClest is estimated creatinine clearance in mL/min,
 Age is in years,
 BW is body weight in kg, and
 SCr is serum creatinine in mg/dL.
 The 0.85 correction factor for females is present because
women have smaller muscle mass than men and, therefore,
produce less creatinine per day.
188
 
 
cr
est
S
BW
age
CrCl



72
140
85
.
0

impairment…
• Example: a 55-year-old, 80-kg, 5-ft 11-in male has a serum
creatinine equal to 1.9 mg/dL. Calculate the creatinine
clearance
 IBW males=50 +2.3 (Ht −60) =50 +2.3(71 −60) =75 kg,
so the patient is within 30% of his ideal body weight
and the Cockcroft-Gault method can be used;
 CrClest =[(140 −age)BW] / (72 ⋅ SCr) =[(140 −55 y)80 kg]
/ (72 ⋅ 1.9 mg/dL) =50 mL/min.
189

impairment…
• Dose adjustment as per creatinine clearance
 Creatinine clearance is <50−60 mL/min- modest decrease in drug doses
 Creatinine clearance is <25−30 mL/min, a moderate decrease in drug doses
 Creatinine clearance is ≤15 mL/min, a substantial decrease in drug doses.
190

impairment…
• Ways to adjust doses for patients with renal impairment,
 Decrease the drug dose and retain the usual dosage interval,
 E.g. Drugs given parenterally
 Retain the usual dose and increase the dosage interval,
 E.g. Drugs given orally
 Simultaneously decrease the dosage and prolong the dosage
interval.
 E.g. Drugs with narrow therapeutic ranges
191

Dosage regimen adjustment in
hepatic impairment
• Most lipid-soluble drugs are metabolized to some degree by
the liver
• In severe liver diseases, several pharmacokinetic parameters
are affected:
 Decrease in overall drug clearance
 Higher BA for drugs having first pass effect
 Production of albumin decreases
 Free fraction of drugs in the blood increases
192

hepatic impairment…
• High concentration of bilirubin in the blood
 Displaces drug from plasma protein binding sites
 Increase free fraction of drug in the blood
• There is no single laboratory test that can be used to assess liver
function in the same way that measured or estimated
creatinine clearance is used to measure renal function.
 Generally speaking, drug dosage should be reduced in patients with
hepatic dysfunction since clearance is reduced and availability increased
193

• When infants are born, renal function is not yet completely
developed in full-term neonates (~40 weeks gestational age).
• Kidney development is complete and renal function stabilizes
3–6 months after birth.
• Hepatic metabolism of drugs is not completely developed in
neonates (~40-weeks gestational age), and continues to
increase so that by age 3–6 months it is stable.
194
pediatrics

• The child dose can be calculated from adult dose by using the following
equation:
195
pediatrics
dose
Adult
m
in
child
of
SA
dose
Child 

73
.
1
2
   
60
2
/
1
2 weight
height
m
in
SA



• Drugs dose should be reduced in elderly patients because of a
general decline in body function with age.
 Decline in kidney function and hepatic function
• The lean body mass decreases and body fat increases by
almost 100% in elderly persons as compared to adults
• There is smaller volume of body water in elderly
 Vd of a water soluble drugs may decrease
 Vd of lipid soluble drugs increase with age
196
Dosage regimen adjustment in elderly

• A dose adjustment can be made using :
197
Dosage regimen adjustment in elderly
    dose
Adult
years
in
Age
Kg
in
Weight
dose
s
Patient 


1660
140
'
7
.
0

obesity
• Any person whose body weight is more than 25% above
the IBW is considered obese.
 IBWmales(In Kg)=50 + 2.3 (Ht-60)
 IBWfemales (in Kg)= 45 + 2.3 (Ht-60), Ht is height in
inches
 In such patients, the lean to adipose ratio is small because
of greater proportion of body fat
198

• Pharmacokinetic parameters affected in obesity include
 Alteration in volume distribution
 The volume of distribution of highly lipid soluble drugs can be
dramatically larger than in normal weight patients because these
drugs tend to partition into adipose tissue
 diazepam, carbamazepine, and trazodone
 Hydrophilic drugs tend to not distribute into adipose tissue so that the
volume of distribution for many water-soluble drugs is not
significantly different in obese and normal weight patients.
 digoxin, cimetidine, and ranitidine 199
obesity

 Increased glomerular filtration rates
 This alteration primarily affects hydrophilic drug
compounds that are renally eliminated and will increase
the renal clearance of the agent.
 Variable effects on the metabolism of drugs.
 For many agents(carbamazepine & cyclosporine) obesity
does not significantly affect hepatic clearance.
 While for other drugs (diazepam), obesity increases
hepatic clearance or decreases metabolic clearance, eg.
methylprednisolone
200
obesity

Pharmacokinetic drug interactions in
combination therapy
• Pharmacokinetic drug interactions occur between drugs
when one agent changes the clearance or volume of
distribution of another medication.
• There are several drug interaction mechanisms that result in
altered drug clearance
 A drug can inhibit or induce the enzymes responsible for
the metabolism of other drugs
201

 Enzyme inhibition decreases intrinsic clearance, and
enzyme induction increases intrinsic clearance
 If two drugs are eliminated by the same enzyme, they
may compete for the metabolic pathway and decrease
the clearance of one or both compounds.
202
Pharmacokinetic drug interactions
in combination therapy…

 By virtue of its pharmacologic effect, a drug may increase
or decrease blood flow to an organ that eliminates or
metabolizes another medication and thereby decrease the
clearance of the medication.
 Another type of drug interaction displaces a drug from
plasma protein binding sites because the two compounds
share the same binding site, and the two compete for the
same area on plasma proteins.
203

 Changes in plasma protein binding also cause alterations
in volume of distribution.
 If two drugs share the same tissue binding sites, it is possible
for tissue-binding displacement drug interactions to occur
and change the volume of distribution for one of the
medications.
 Half-life may change as a result of drug interactions
204

205
IV. Therapeutic drug monitoring

• The therapeutic range for a drug is an approximation of the
average plasma drug concentrations that are safe and
efficacious in most patients.
• However, large differences have been reported in individual
patient response to treatment with a given drug
 The therapeutic concentration of a drug in one individual
may prove to be sub-therapeutic concentration in another
individual, and toxic concentration in somebody else.
206
Introduction

Introduction…
• For example, the accepted therapeutic range for
theophylline is 10–20 g/mL.
 Some patients may exhibit signs of theophylline
intoxication such as central nervous system excitation
and insomnia at serum drug concentrations below 20
g/mL
 Whereas other patients may show drug efficacy at
serum drug concentrations below 10 g/mL.
207

Introduction…
 To address such problems therapeutic drug monitoring
(TDM) or clinical pharmacokinetic (laboratory) services
(CPKS) have been established in many hospitals to evaluate
the response of the patient to the recommended dosage
regimen.
• TDM, the measurement and interpretation of drug
concentration, has been used to individualize drug therapy
since the early 1970s
208

Introduction…
• The aim of TDM is to optimize pharmacotherapy by maximizing therapeutic
efficacy, while minimizing adverse events.
• The improvement in the clinical effectiveness of the drug by TDM may decrease
the cost of medical care by preventing untoward adverse drug effects
209

Introduction…
• Drugs monitored by TDM
 Drugs with dangerous toxicity
 Drugs having narrow therapeutic range
 Drugs used in long term therapy
 Drugs used in life threatening disease
 Drugs having interindividual pharmacokinetic variability
 Drugs with nonlinear pharmacokinetics
 Drugs with wide distribution in the body
210

Drugs with TDM-guided dosing
211

212
End of Biopharmaceutics and Clinical pharmacokinetics course
Thank You!

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