TMAX - AN UNCONFOUNDED METRIC FOR RATE OF ABSORPTION IN SINGLE-DOSE BIOEQUIVALENCE STUDIES

Purpose. While peak drug concentration (Cmax) is recognized to be cont aminated by the extent of absorption, it has long served as the indica tor of change in absorption rate in bioequivalence studies. This conce ntration measure per se is a measure of extreme drug exposure, not abs orption rate. This paper redirects attention to Tmax as the absorption rate variable. Methods. We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected a bsorption phase, defines a count process which encapsulates the rate o f absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measur es based on Cmax to evaluate only for dose-dumping, a legitimate safet y concern with any formulation. These principles and techniques are il lustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. Results, Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, wherea s the customary analysis with Cmax leads to rejection of bioequivalenc e. This suggests that the inappropriate use of Cmax as a surrogate met ric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.