Metrics Comparing Simulated Early Concentration Profiles for the Determination of Bioequivalence

Abstract

Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles.

Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC _P) the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I _{L /H}), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (M _log). For comparison, also properties of C _maxand an ideally evaluated measure (Id) were determined.

Results. M _logshowed generally the highest statistical power and KS, and also the largest SE, closely followed by I _{L /H}. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C _max. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation.

Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M _loghad the highest statistical power, closely followed by I_{L /H}and then by partial AUC.