Metrics comparing simulated early concentration profiles for the determination of bioequivalence.

Abstract

To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Two-period crossover trials were simulated with increasing assumed ratio 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(AUCP), 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 (MLOG). For comparison, also properties of CMAX and an ideally evaluated measure (Id) were determined. MLOG showed 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 CMAX. 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. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. MLOG had the highest statistical power, closely followed by I L/H and then by partial AUC.