Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies

Abstract

As indirect measures of rate of drug absorption (metrics), maximum plasma concentration (Cmax) is confounded by extent of drug absorption and the time to reach Cmax (tmax) is a discrete variable, dependent on blood sampling frequency. Building on the work of Endrenyi et al., we have compared different metrics, including Cmax/area under the curve of concentration versus time from time zero to infinity (AUC infinity), partial AUC from zero to tmax (AUCp), and Cmax.tmax with simulated experiments. Importantly, the performance of these metrics was assessed with the results of actual pharmacokinetic studies involving Glaxo drugs. The results of the simulated and real experiments were consistent and produced the following unambiguous findings: (1) Cmax/AUC infinity is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent; (2) Cmax/AUC infinity is more sensitive than Cmax at detecting differences in rate of absorption when they exist; and (3) the treatment ratios for AUCp, AUCp/AUC infinity, and Cmax.tmax are very imprecisely estimated and are of no practical value as measures of rate of absorption. Of the metrics examined, Cmax/AUC infinity is the most sensitive and powerful indirect measure of rate of drug absorption in comparative pharmacokinetic studies involving immediate-release dosage forms and should be used instead of Cmax in bioequivalence testing.