Brief introduction to bioavailability

Objectives of bioavailability

Methods of assessing bioavailability

Concept of equivalence

References
 Introduction

• Bioavailability is defined as rate and extent of absorption of

unchanged drug from it’s dosage form and become available
at
the site of action.

•Bioavailability of a drug from it’s dosage form depends upon 3

major factors:
 Pharmaceutical factors
 Patient related factors
 Route of administration
 Objectives
 Development of new formulations.

 Determination of influence of excipients, patient related

factors and possible interaction with other drugs on the
efficiency of absorption.

 Control of quality of a drug product during the early stages of

marketing in order to determine the influence of processing
factors, storage, stability on drug absorption.

 Primary stages of the development of a suitable dosage form

for a new drug entity.
•When systemic availability of drug administered orally is
determined in comparison to its intravenous administration, is called
absolute bioavailability.

•Its determination is used to characterize a drug’s inherent

absorption properties from the extra vascular site.

Absolute bioavailability = [AUC]oral (Dose)iv

[AUC]iv (Dose)oral
Relative Bioavailability (Fr)

• When systemic availability of drug after oral administration is

compared with that of an oral standard of same drug (such as an
aqueous or non aqueous solution or suspension) it is referred as
relative bioavailability.

• It is used to characterize absorption of drug from its formulation.

Relative Bioavailability = [AUC]test (Dose)std

[AUC]std (Dose)test
• Widely used and based on assumption that Pharmacokinetic
profile reflects the therapeutic effectiveness of a drug.

Plasma Level- Time Studies:

• Most common type of human bioavailability studies.

• Based on the assumption that there is a direct relationship

between the concentration of drug in blood or plasma and the
concentration of drug at the site of action.

• Following the administration of a single dose of a

medication, blood samples are drawn at specific time intervals
and analyzed for drug content.
• 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)
Area under curve
Plasma Drug Concentration- Time Profile
 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
mg/ml.
 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.
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 &
t = ∞, and is equal to the amount of unchanged drug reaching the
general circulation divided by the clearance.

[ AUC]0∞ = ∫0∞Cpdt

[ AUC]0∞ = FDO/ kVD

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

is
= C1 +C2
•

Thus AUC = C1+C2 (t2-t1) C2+C3 (t3-t2) +……

+ 2 2
...Cn-1+ Cn (tn+1-tn)
2.
• The extent of bioavailability can be determined by the following
equations:
For single dose study:

For multiple dose study:

Urinary Excretion Studies:

• Urinary excretion of unchanged drug is directly proportional to

plasma concentration of drug.

• Thus, even if a drug is excreted to some extent (at least 10 to

20%) in the urine, bioavailability can be determined.
eg: Thiazide diuretics, Sulphonamides.

• Method is useful when there is lack of sufficiently sensitive

analytical technique to measure drug concentration.

• Noninvasive method, so better patient compliance.

(dxu/dt)max :(Maximum urinary excretion rate)
• Its value increases as rate and/or extent of absorption increases.
• Obtained from peak of plot between rate of excretion
versus midpoint time of urine collection period.
(tu) max:
• Time for maximum excretion rate
• Its value decreases as absorption rate increases.
• Analogues of tmaxof plasma level data.

Xu:Cumulative amount of drug excreted in urine

∞
• Related to AUC of plasma level data.
• It increases as the extent of absorption increases.
The extent of bioavailability is calculated from equation :

For single dose study:

For multiple dose study:

Acute Pharmacologic Response Method:

• When bioavailablity measurement by pharmacokinetic method is

difficult, an acute pharmacologic effect such as effect on
pupil diameter, EEG & ECG readings
related to time course of drug.
• 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.
 Therapeutic Response Method:
• This method based on observing the clinical response to a drug
formulation given to patient suffering from disease.

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.
E.g.: Anti-inflammatory drugs.

 Many patients receive more than one

drug
• Clinical trails in humans establish the safety and effectiveness of
the drug products and also used to determine bioavailability.

• The FDA consider 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 product.
Ex: Ketoconazole
• Drug dissolution studies may under certain conditions give an
indication of drug bioavailability.

• Dissolution studies are often performed in several test

formulations of the same drug.

• The test formulation that demonstrates the most rapid rate of drug
bioavailability in-vitro will generally have the most rapid rate of
drug bioavailability in-vivo.

• The FDA may also use the other in-vitro approaches for
establishing bioequivalence.
Ex: Cholestyramine resin.
 CONCEPT OF EQUIVALENCE:

EQUIVALENCE: Relationship in terms of bioavailability,

therapeutic response or a set of established standards of one drug
product to 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) A risk of bio-inequivalence.
Equivalence may be defined in several
ways:
Chemical
 equivalence:
If two or more dosage forms of same drug contain same labelled
quantities specified in pharmacopoeia.
Eg : 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 the same relative rate and
extent i.e. their plasma concentration-time profiles will be
identical without significant statistical differences.
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.
Eg : Chlordiazepoxide hydrochloride,5mg capsules.

Pharmaceutical equivalent drug products are:

Same in :
 Active ingredient and it’s quantity
 Dosage form
 standards like strength, quality , purity and identity.
 Disintegration time
 Dissolution rates

Differ in:
 Shape
 Release
 mechanisms
 Packing
 Excipients(including colours , flavours , preservatives)
labeling
 Pharmaceutical alternatives:
 Drug product that contain the same therapeutic moiety but as
different salts, esters or complexes.
Eg: Tetracyclin phosphate or Tetracyclin hydrochloride
equivalent to 250mg Tetracyclin base are consider as
pharmaceutical alternatives.

pharmaceutical substitution:
 The process of dispensing a pharmaceutical alternative for the
prescribed drug product.
Eg: Ampicillin suspension is dispensed in place of Ampicillin
capsules.
Tetracyclin hydrochloride is dispensed in place of Tetracyclin
phosphate.
NOTE: Pharmaceutical substitution generally requires the
physician’s approval.
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 labeling.

 FDA classifies as therapeutically equivalent those products that

meet the fallowing general criteria:
1)They approved as safe and
effective. 2)They are pharmaceutically
equivalents. 3)They are
bioequivalence.
4) They are adequately labeled .
5)They are manufactured in compliance with current
Therapeutic alternatives:
Drug products containing different active ingredients that are
indicated for the same therapeutic or clinical objectives.
Eg: Ibuprofen is given instead of Aspirin.
Cimetidine instead of Ranitidine.

Therapeutic substitution:
The process of dispensing a therapeutic alternative in place of the
prescribed drug product.
Eg: Ampicillin is dispensed instead of Amoxicillin.
Ibuprofen is dispensed instead of Naproxen.