M.Pharm 2nd semester

1. Clinical significance of
bioequivalence study
Submitted by, Submitted to,
Mohd Sufiyan Dr. Poonam Kushwaha
M.Pharm (Pharmaceutics)

2. Bioequivalence
• It is a relative term which denotes that the drug substance in
two or more identical dosage forms, reaches the systemic
circulation at the same relative rate and to the same relative
extent i.e. their plasma concentration-time profiles will be
identical without significant statistical differences.
• When statistically significant differences are observed in the
bioavailability of two or more drug products, bio-
inequivalence is indicated.
• The absence of a significant difference in the rate and extent to
which the active ingredient or active moiety in pharmaceutical
equivalents or pharmaceutical alternatives becomes available
at the site of drug action when administered at the same molar
dose under similar conditions in an appropriately designed
study.

3. Clinical Significance

4. Products Require BE Studies
Products requiring be studies are mainly
 drugs with narrow margin of safety,
e.g. digoxin, antiarrhythmic, anticoagulants, cytostatics,
lithium, phenytoin, cyclosporine, sulphonylureas, theo- phylline
 critical use drugs, i.e. drugs indicated for serious conditions
requiring assured therapeutic response,
e.g. antiinfectives, cardiovascular drugs, antiepileptics,
antiasthmatics; and
 sustained or modified release products, due to the difficult
formulation.

5. Drug Interchangeability
• In practice, bioequivalence in drug absorption has been
interpreted that the confidence interval for the ratio of means
(of drug absorption) is within bioequivalence limits.
• The FDA, however, does not indicate that approved generic
drug products and the innovative drug products can be used
interchangeably.
• The FDA only indicates that an approved generic drug product
can be used as a substitute to the innovative drug product.
• Basically, drug interchangeability can be classified either as
a. drug prescribability or
b. drug switchability

6. Comparing Generic and Innovator Drugs
Bioequivalence (BE) study is required to show whether a generic
copy product can be interchangeable with the brand innovator
product.
E.g.: BE studies of clopidogrel generics :
• Clopidogrel is a prodrug that must undergo hepatic metabolism
to become the active metabolite.
• The active metabolite is highly unstable and thus difficult to
measure.
• Therefore, the BE study of clopidogrel may be a
pharmacokinetic study or a pharmacodynamic study.
• The pharmacokinetic BE study of clopidogrel is based on the
measurement of clopidogrel parent compound.

7. Drug Formulations
• Bioequivalence for most of oral tablets or capsules is
demonstrated in vivo by comparing the rate and extent of
absorption that is bioavailability of the generic product with
that of the innovator product.
• This is done by measuring the active ingredient concentration
in blood, plasma, serum or other biological fluids over a
certain period of time for both the generic and innovator
products, also called test and reference drugs respectively.
• By doing so the bioequivalence studies frequently rely on
pharmacokinetic measures such as area under the
concentration-time curve (AUC) and peak drug concentration
(Cmax)

8. Drug Development
• Bioequivalence studies are very important for the development
of a pharmaceutical preparation in the pharmaceutical industry.
• Their rationale is the monitoring of pharmacokinetic and
pharmacodynamics parameters after the administration of
tested drugs.
• The target of such study is to evaluate the therapeutic
compatibility of tested drugs (pharmaceutical equivalents or
pharmaceutical alternatives).

9. Clinical Interpretation
• Clinical interpretation is important in evaluating the results of
a bioequivalence study.
• Bioequivalence studies should be conducted for the
comparison of two medicinal products containing the same
active substance.
• Two products marketed by different licensees, containing same
active ingredient(s), must be shown to be therapeutically
equivalent to one another in order to be considered
interchangeable.
• Differences of less than 20% in AUC & Cmax between drug
products are unlikely to be clinically significant in patients.
• Minimize product to product variability by different
manufactures & lot to lot variability with a single manufacture.

10. Reference
1. Palylyk-Colwell E, Jamali F, Dryden W, Friesen E et al.:
Bioquivalance and interchangeability of narrow therapeutic range
drugs. Canadian Society of Pharmaceutical Sciences Discussion 1.
Journal of Pharmacy and Pharmaceutical Sciences. 1998 (in press).
2. Wagner JG, Welling PG, Lee KP and Walker JE: In vivo and in
vitro availability of commercial Warfarin tablets. Journal of
Pharmaceutical Sciences. 1971;60:666-677.
3. Ruedy J, Davies RO, Gagnon MA, McLean WM, Thompson WG,
Vitti TG, et al: Drug bioavailability. Canadian Medical Association
Journal. 1976;115:105.
4. McGilveray IJ, Midha KK, Cooper JK: Bioavailability of Canadian
tablet formulations of Warfarin Sodium and Potassium. Canadian
Journal of Pharmaceutical Sciences. 1978;13:9-11. 5. Muller FO,
Steyn JM, Hundt HKL, Luus HG: Warfarin bioavailability, a
comparison of four products. South African Medical Journal.
1988;74:566-567.

11. Thank You…