ACCEPTABLE AND UNACCEPTABLE PROCEDURES IN BIOAVAILABILITY AND BIOEQUIVALENCE TRIALS

Abstract Both the US FDA and EU guidelines recommend fundamental procedures for bioavailability and bioequivalence studies. The use of unacceptable procedures in conducting these studies can in fact complicate drug development at NDA or ANDA levels. The most common unacceptable procedures are as follows: the use of compartmental analysis in calculating C max , t max and AUC, which must be evaluated with the non-compartmental approach in pivotal studies; the need to use only homogeneous concentrations in pharmacokinetic analysis, and to avoid using the sum of various individual concentrations, e.g. parent drug plus metabolite(s); the need to consider plasma clearance in evaluating absolute bioavailability with dose-dependent kinetics; the need to use the simultaneous fitting procedure when drugs and metabolite(s) are considered; the unacceptable procedure of either disregarding some experimental data or adding simulated data in pharmacokinetic and statistical analysis; and the use of the additive model rather than the multiplicative procedure in assessing bioequivalence with C max and AUC. This paper describes in detail acceptable and unacceptable procedures in bioavailability and bioequivalence studies, covering operating guidelines and principles of pharmacokinetics.