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

As indirect measures of rate of drug absorption (metrics), maximum pla sma concentration (C-max) is confounded by extent of drug absorption a nd 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 cur ve of concentration versus time from time zero to infinity (AUC(infini ty)), partial AUC from zero to t(max), (AUC(p)) and C-max.t(max) with simulated experiments. Importantly, the performance of these metrics w as assessed with the results of actual pharmacokinetic studies involvi ng 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 bi oequivalence 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 A UC(p), AUC(p)/AUC(infinity), and C-max.t(max) are very imprecisely est imated and are of no practical value as measures of rate of absorption . Of the metrics examined, C-max/AUC(infinity) is the most sensitive a nd 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.