Bioequivalence: How, Why, and What Does it Really Mean?

Abstract

Aim: To review the pharmacokinetic and pharmacodynamic principles of bioequivalence testing of medicines administered orally to achieve a systemic effect. This includes methods used to estimate bioequivalence, practical implications of the expected variability in drug concentration‐time profiles from bioequivalent formulations and other sources of variability which influence drug absorption and therapeutic response.Method: The impact of sample size, pharmacokinetic variability and expected differences in relative bioavailability are examined with respect to relevant literature and using simulations. The variability in drug concentration‐time profiles following different formulations of the same active ingredient is compared to other sources of variability affecting drug delivery to its site of action.Results: The use of comparative drug concentration‐time profiles to establish the bioequivalence of two orally administered formulations is based on well‐established and thoroughly tested scientific principles. Formulations with variability in drug concentration‐time profiles greater than 10% are unlikely to satisfy the statistical standards defining bioequivalence. Inter and intra batch‐to‐batch variability in active substance content of oral formulations limits specifying dissolution rate and plasma concentration ranges defining therapeutic effect of specific drugs may exceed the limits applied to defining bioequivalence and hence may contribute to differences in patient response after administration of different medicinal products. These standards are within the scope of other sources of variability which limit the predictability of therapeutic response to blood levels for individual patients. These include acceptable levels of variability of the amount of active ingredient within and between batches, tablet dissolution rates and poorly defined therapeutic blood levels for many drugs.Conclusion: The methods used to determine bioequivalence have stood the test of time. The criteria used to assess bioequivalence mean that the differences in actual drug concentration‐time profiles obtained with a generic or originator formulation are small and certainly less variable than other factors that contribute to variability in response.