EVALUATION OF DIFFERENT INDIRECT MEASURES OF RATE OF DRUG ABSORPTION IN COMPARATIVE PHARMACOKINETIC STUDIES

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