The application of partial areas in assessment of rate and extent of absorption in bioequivalence studies of conventional release products: experimental evidence

Abstract

A bioequivalence study on perphenazine/amitriptyline combination compared three formulations (TST-1, TST-2 and REF) containing the same nominal dose of perphenazine, while TST-2 contained 20% less amitriptyline than the other two formulations. ANOVA-SNK on log-transformed partial areas AUC 0 24 through AUC 0 ∞ showed the intra-subject variabilities of perphenazine to be consistently higher than those of amitriptyline or nortriptyline. There was also a marked increase in intra-subject variability for perphenazine on extrapolating AUC 0 last to infinity. Thus, whhile the 1–2α confidence intervals (90% CIs) and ratios of geometric means for perphenazine fell within preset limits of 80–125% in all pairwise comparisons, the CIs for AUC 0 ∞ violated the upper limit in comparisons of TST-2 and REF (or TST-2 and TST-1). This outcome could be attributed to high intra-subject variability on AUC 0 ∞. ANOVA-SNK of amitriptyline identified a significant difference in extent of amitriptyline absorbed from TST-2 compared with TST-1 and REF. Thus, in pairwise comparisons between TST-1 and REF, all 90% CIs for amitriptyline partial areas AUC 0 4 through AUC 0 ∞ fell within 80–125% limits. In corresponding comparisons between TST-2 and REF (or TST-2 and TST-1), however, the lower limit of the 90% CIs for AUC 0 1 through AUC 0 last consistently fell below the 80% cut off. By contrast, 90% CIs associated with the ratios C max/AUC 0 4 through C max/AUC 0 ∞ all fell within preset limits indicating no differences in absorption rate of amitriptyline, consistent with the theoretical argument that C max/AUC is influenced by rate but not extent of absorption. Thus the partial area method is applicable to the evaluation of both relative rate and extent of absorption from conventional release products. Similarly, analyses of nortriptyline data showed that the partial area method is also effective in the evaluation of rate and extent of formation of a metabolite in a bioequivalence study. The partial area method permits a greater number of plasma samples to be devoted to accurate estimation of t max and C max since the necessity to estimate AUC 0 ∞ is obviated.