ACCEPTABLE AND UNACCEPTABLE PROCEDURES IN BIOAVAILABILITY AND BIOEQUIVALENCE TRIALS

Both the US FDA and EU guidelines recommend fundamental procedures for bioavailability and bioequivalence studies. The use of unacceptable p rocedures in conducting these studies can in fact complicate drug deve lopment at NDA or ANDA levels. The most common unacceptable procedures are as follows: the use of compartmental analysis in calculating C-ma x, t(max) and AUC, which must be evaluated with the non-compartmental approach in pivotal studies; the need to use only homogeneous concentr ations in pharmacokinetic analysis, and to avoid using the sum of vari ous individual concentrations, e.g. parent drug plus metabolite(s); th e need to consider plasma clearance in evaluating absolute bioavailabi lity with dose-dependent kinetics; the need to use the simultaneous fi tting procedure when drugs and metabolite(s) are considered; the unacc eptable procedure of either disregarding some experimental data or add ing simulated data in pharmacokinetic and statistical analysis; and th e use of the additive model rather than the multiplicative procedure i n 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 o f pharmacokinetics. (C) 1998 The Italian Pharmacological Society.