Bioavailability is a measure of the rate and fraction of the initial dose of a drug that successfully reaches either; the site of action or the bodily fluid domain from which the drug’s intended targets have unimpeded access. For majority purposes, bioavailability is defined as the fraction of the active form of a drug that reaches systemic circulation unaltered. This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site. However, it should be appreciated that this definition is not inclusive of drugs that do not require access to systemic circulation for function (i.e., certain topical drugs). The bioavailability of these drugs is measured by different parameters discussed elsewhere.

1. BIOAVAIL ABILIT Y,
PHARMACOKINETICS AND
EFFICACY DETERMINATION
PRESENTED B Y
SALUM MKATA
R.PHARM.

3. INTRO…………
• Bioavailability is a measure of the rate and fraction of the initial
dose of a drug that successfully reaches either; the site of action
or the bodily fluid domain from which the drug’s intended
targets have unimpeded access.
• For majority purposes, bioavailability is defined as the fraction
of the active form of a drug that reaches systemic circulation
unaltered. This definition assumes 100% of the active drug that
enters systemic circulation will successfully reach the target site.
However, it should be appreciated that this definition is not
inclusive of drugs that do not require access to systemic
circulation for function (i.e., certain topical drugs). The
bioavailability of these drugs is measured by different
parameters discussed elsewhere.

4. INTRO………
• Bioavailability is an integral part of the pharmacokinetics
paradigm. Pharmacokinetics is the study of drug movement
through the body and is often represented by the acronym
ABCD which stands for Administration, Bioavailability,
Clearance, and Distribution.
• Administration refers to the route and dosing of a drug.
Clearance is the active form of a drug being removed from the
systemic circulation. Distribution measures how widely a drug
can travel to fluid compartments of the body; this definition
assumes distribution follows absorption if taken orally.

5. TYPES OF BIOAVAILABILITY
• Absolute bioavailability (F):-
• Absolute bioavailability compares the bioavailability of the
active drug in systemic circulation following non-intravenous
administration, with the bioavailability of the same drug
following intravenous administration
• For drugs administered intravenously, bioavailability is 100%.
• Determination of the best administration route.

6. TYPES OF BIOAVAILABILITY

7. TYPES OF BIOAVAILABILITY
• Relative Bioavailability (Fr)
Relative bioavailability measures the bioavailability (estimated as
the AUC) of a formulation (test) of a certain drug when
with another formulation (standard) of the same drug, usually an
established standard, or through administration via a different
route.

8. TYPES OF BIOAVAILABILITY
• Range of Bioavailability – 0 to 1.
• It is usually expressed as percentages (%).
• An absolute bioavailability of 1(or 100%) indicates
complete absorption.
• Relative bioavailability of 1 (or 100%) implies that the
bioavailability of drug from both the dosage forms is
the same but does not indicate the completeness of
the systemic drug absorption.

9. FACTORS AFFECTING BIOAVAILABITY
Bioavailability of a drug from it’s dosage form depends upon 3
major factors;
Pharmaceutical factors
Patient related factors /Physiological factors
Miscellaneous (e.g. Route of administration)

10. FACTORS AFFECTING DRUG
ABSORPTION
• PHYSIOLOGICAL
FACTORS
PATIENT RELATED
FACTORS
• PHYSICO-CHEMICAL
FACTORS
• DOSAGE FORM
FACTORS
PHARMACEUTICAL
FACTORS
Miscellaneous

11. 1.PHARMACEUTICAL FACTORS
It is expected that, bioavailability of drugs to be in
this decreasing order-
Solutions > Suspension > Capsule > Tablet > Coated
Tablet

12. THE PHARMACEUTICAL FACTORS
INCLUDE:
– Particle Size
• The rate at which a drug is dissolved can be increased by increasing its surface area
by decreasing its PARTICLE SIZE.
– Salt Form
• The rate at which a particular salt dissolves differs from its parent compound.
• Salts of weakly acidic drugs are highly water soluble, free acidic drugs is
precipitated from these salts is micro crystalline form, which has a faster dissolution
rate and increases bioavailability.
– Crystal Forms
• The rate of absorption and bioavailability of a drug also depends on its crystalline
form.
• This is because amorphous forms dissolve faster compared to crystalline forms,
because no energy is needed to break up the crystalline lattice, thus increasing
their bioavailability.

13. CONTINUED……
― Water of Hydration
• Many drugs incorporate water to produce a crystalline form called hydrates.
• If water molecules are already present in a crystal structure, the tendency of
the crystal to attract additional water to initiate dissolution process is reduced,
compared to anhydrous forms.
– Nature of Excipients and Adjuvants
• These pharmacologically inert substances , (e.g starch, lactose, calcium sulfate,
gum) which are added as filling material or as binding agents or to obtain
proper granular size, have tremendous effects on bioavailability of drugs.
• Some of these excipients are wetting agents, which enhance solvent penetration
and ensures faster dissolution and in turn absorption.
• We should be particularly careful in drugs which follows zero order or mixed
order kinetics or have a low margin of safety.
– Degree of Ionisation
• Non-ionised, lipid soluble drugs are better absorbed, increasing their
bioavailability, compared to strongly acidic or strongly basic drugs or highly ionised
drugs.

14. 2. PATIENT RELATED FACTORS /PHYSIOLOGICAL
FACTORS:
– Gastric Emptying and Gastrointestinal Motility
• Factors that accelerate gastric emptying increases the bioavailability. This is because
the drug is exposed to the larger surface area of the small intestine.
• High motility(e.g diarrhea) the drug has a shorter residence time and less absorbed
– Gastrointestinal Diseases
• There are many gastrointestinal diseases which have an effect on drug absorption,
the outcome of Coeliac disease is complex, it increases the absorption of cephalexin,
whereas reduces of amoxicillin.
• In case of Crohn’s disease, there is disproportionate absorption of individual
components of cotrimoxazole, increases absorption of sulfamethoxazole, decreases of
trimethoprim
– Food and Other Substances
• In general, GI absorption rate is reduced after ingestion of food, although it has no
effect on extend of absorption.
• Both rate and extend of absorption of certain antibiotics like rifampicin is reduced after
meals.
• Absorption of tetracyclines is reduced if taken with milk because it forms poorly
absorbed complexes with calcium.
• Vit. C increases absorption of iron because it keeps it in it’s ferrous form.

15. – First Pass Metabolism
• It means that drug degradation occurs, reducing its
bioavailability, when it passed through GIT wall and then through
portal system, before it reaches systemic circulation.
– Drug-Drug Interactions
• Drug-drug interactions can also cause difference in bioavailability.
• Liquid paraffin decreases the bioavailability of fat soluble
vitamins as it emulsifies fat.
• Antacids reduces bioavailability of tetracyclines because it forms
chelated complex.
– Pharmacogenetic Factors
• Large difference in bioavailability often occurs among
humans due to pharmacogenetic reasons.
• Slow and fast acetylators show increased and decreased
bioavailability of isoniazid respectively.

16. 3.MISCELLANEOUS FACTORS
• Area of Absorptive Surface
• State of Circulation at the Site of Absorption (shock, where tissue
perfusion decreases)
• Route of Administration

17. METHODS OF ASSESSING BIOAVAILABILITY:
• Pharmacokinetic methods (indirect)
1. Blood analysis
2. Urinary excretion data
• Pharmacodynamic methods (direct)
1. Acute pharmacological response
2. Therapeutic response

18. PHARMACOKINETIC METHODS
• Widely used and based on assumption that Pharmacokinetic
profile reflects the therapeutic effectiveness of a drug.
1. Blood analysis
• Plasma level time studies or The plasma concentration – time
curve or blood level curve.
• A direct relationship exists concentration of drug at the site of
action & concentration of drug in the plasma.
• Serial blood samples are taken after drug administration &
analyzed for drug concentration.
• A typical blood level curve obtained after oral administration of
drug.

19. CONTINUED
• A profile is constructed showing the concentration of drug in
blood at the specific times the samples were taken.
• Bioavailability (the rate and extent of drug absorption) is
generally assessed by the determination of following three
parameters.
They are….. Cmax (Peak plasma concentration)
tmax (Time of peak)
AUC (Area under curve)

20. CONTINUED……..

21. IMPORTANT PK PARAMETERS FOR
DOCUMENTING BE-PLASMA LEVEL TIME
• Drug plasma concentration time profile- sampling should be extended
for at least 3 elimination t1/2

22. PK PARAMETERS FOR BE CONT….
SINGLE DOSE
Cmax: (Peak plasma drug concentration)
 Maximum concentration of the drug obtained after the
administration of single dose of the drug.
 Expressed in terms of µg/ml or ng/ml or mg/L
 Indicator of rate of absorption.
Tmax : (Time of peak plasma conc.)
 Time required to achieve peak concentration of the drug after
administration.
 Gives indication of the rate of absorption.
 Expressed in terms of hours or minutes.

23. CONTINUED
AUC: Is the measurement of the extent of the drug bioavailability
 It is the area under the drug plasma level-time curve from t=0
and t=α, an is equal to the amount of unchanged drug
the general circulation divided by the clearance.
 Expressed in terms of µg/ml x hrs or ng/ml x hrs or mg/L x hrs
 Indicator of extent of absorption

24. MEASUREMENT OF AUC
1.Trapezoidal method:
 Most common method of estimating AUC.
 Divide the plasma conc-time curve into several trapezoids.
 Count the trapezoids and find the area.
 Total area of the trapezoids will approximate the area under the
curve.
 More number trapezoids formed more accurate will be the result.
The area of one trapezoid between time t1 and t2 is

25. MEASUREMENT OF AUC

26. MEASUREMENT OF AUC
2.Planimeter:
• Instrument for mechanically measuring the area under the
curve.
• Measures area by tracing outline of curve.
Disadvantage:
• Degree of error is high due to instrumental and human error

27. MEASUREMENT OF AUC
3.Cut and weigh method:

28. MEASUREMENT OF AUC
4.Counting the squire:
• Total no. of squares enclosed in the curve is counted.
• Area of each squire determined using relationship:
AREA=(height) (width)

29. PHARMACOKINETIC METHODS
2. Urinary excretion data
• Urinary drug excretion data is an indirect method for estimating rate and
extent of absorption.
Assumption: Urinary excretion of unchanged drug is directly proportional
to plasma concentration of drug.
• The drug must be excreted in significant quantities as unchanged drug in
the urine (at least 10-20%) e.g.: Thiazide diruretics, sulphonamides.
• Timely urine samples must be collected and the total amount of urinary
drug excretion must be obtained
• Method is useful when there is lack of sufficiently sensitive analytical
technique to measure drug concentration.
• Completely empty of the urinary bladder is required
• Non invasive method, so better patient compliance.
• Sampling should be extended for at least 7 elimination t1/2

30. Rate
of
drug
excretion
Mid points of time interval
(dXu/dt)max
URINARY DRUG EXCRETION
PROFILE

31. 1. (dXu/dt )max
(maximum urinary
excretion rate)
2. (tu)max
(time for maximum
excretion rate)
3. Du:
(cumulative amount of
drug excreted in urine)
•Value increases as the rate and/or
extent of absorption increases.
•Analogous to Cmax derived from
plasma studies.
•Value decreases as the absorption
rate increases.
•Analogous to t max derived from
plasma studies.
•Value increases as the extent of
absorption increases.
•Related to AUC of plasma level data
PK PARAMETERS OBTAINED FROM
URINARY DRUG EXCRETION STUDIES

32. PHARMACODYNAMIC METHODS
Acute Pharmacologic Response Method:
 When bioavailability measurement by pharmacokinetic method
is difficult, an acute pharmacologic effect such as effect on
diameter, EEG and ECG readings related to time course of
 Bioavailability can then be determined by construction of
pharmacological effect-time curve as well as dose response
graphs.
Disadvantage:
 It tends to be more variable.
 Observed response may be due to an active metabolite whose
concentration is not proportional to concentration of parent
drug.

33. PHARMACODYNAMIC METHODS
Therapeutic Response Method:
• This method based on observing the clinical response to a
formulation given to patient suffering from disease.
e.g: Anti-Inflammatory drugs, the reduction in the inflammation
determined.
Drawbacks:
The major drawbacks of this method is that quantitation of
observed response is too improper to allow for reasonable
assessment of relative bioavailability between two dosage forms
of the same drug,

34. CONCEPT OF EQUIVALENCE
Equivalence: relationship in terms of bioavailability, therapeutic
response or a set of established standards of one drug product
another.
Objectives:
• If a new product intended to be a substitute for an approved
medical product.
• To ensure clinical performance of drugs.
• Equivalence studies are conducted if there is:
a) At risk of bio-inequivalence
b) A risk of Pharmacotherapeutic failure or diminished clinical
safety.

35. CONCEPT OF EQUIVALENCE
Equivalence may be defined in several ways:
Chemical equivalence:
 If two or more dosage forms of same drug contain same
labelled quantities specified in pharmacopeia. E.g: Dilantin and
Eptoin chemically equivalent as they contain same quantity of
phenytoin on chemical assay.
Bioequivalence:
 The drug substance in two or more identical dosage forms,
reaches the systemic circulation at same relative rate and extent
i.e. their plasma concentration-time profiles will be identical
without significant statistical differences.

36. CONTINUED…….
Pharmaceutical equivalents:
• Drug products in identical dosage forms that contain same
active ingredient (s) i.e., the same salt or ester, are of the same
dosage form, use the same route of administration, and are
identical in strength or concentration. e.g.: Azilin (Azithromycin
500 mg) Tablets versus Azuma (Azithromycin 500 mg) Tablets.
Pharmaceutical alternatives:
 Drug product that contain the same therapeutic moiety but as
different salts, esters or complexes. e.g: Tetracycline phosphate
or Tetracycline hydrochloride equivalent to 250 mg Tetracycline
base are consider as pharmaceutical alternatives.

37. CONTINUED…..
Pharmaceutical substitution:
The process of dispensing a pharmaceutical alternative for the
prescribed drug product. e.g.: ampicillin suspension is dispensed
in place of Ampicillin capsules.
Tetracycline HCl is dispensed in place of Tetracycline phosphate.
Note: Pharmaceutical substitution generally requires physician's
approval.

38. CONTINUED……..
Therapeutic equivalents:
 Drug products consider to be therapeutic equivalence only if
they are pharmaceutical equivalence and if they can be
expected to have a same clinical effect and safety profile when
administered to patient specified in the labelling.
Therapeutic alternatives:
 Drug products containing different active ingredients that are
indicated for the same therapeutic or clinical objectives.
e.g: Ibuprofen is given instead of Aspirin.
Cimetidine instead of Ranitidine.

39. CONTINUED……
Therapeutic substitution:
• The process of dispensing a therapeutic alternative in place of
the prescribed drug product.
• E.g. Ampicillin is dispensed instead of Amoxicillin.

40. QUESTIONS
?