Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations.

For immediate release drug formulations the maximum concentration (Cmax), the time to the maximum concentration (tmax), and the ratio Cmax/AUC have been suggested as absorption rate characteristics. Although tmax is easier to interpret as absorption rate characteristic than Cmax and Cmax/AUC, the latter are generally preferred in practice because these characteristics can be observed with higher precision, and are easier to handle statistically than tmax. In this paper we propose a strategy for setting appropriate bioequivalence ranges for tmax and Cmax/AUC, and for choosing the best characteristic for the comparison of absorption rates when planning a bioequivalence study. This involves motivating the bioequivalence range on that scale which is most convenient for that purpose, namely in terms of differences in tmax. Exploiting the pharmacokinetic relationship between tmax and Cmax/AUC this bioequivalence range is then translated into the corresponding bioequivalence range for Cmax/AUC. The characteristic that gives the greatest power to show bioequivalence can then be specified as the primary absorption rate characteristic. For drugs with short elimination half-lives, or short fastest disposition half-lives if the drug concentrations follow a higher compartmental model, Cmax/AUC is the best characteristic, but for drugs with long elimination or fastest disposition half-lives tmax can be superior to Cmax/AUC.