Comparison of absorption rates in bioequivalence studies of immediate release drug formulations

Abstract

For immediate release drug formulations, the maximum concentration (Cmax), the time to the maximum concentration (tmax), the mean residence time (MRT), and recently, the Cmax/AUC ratio have been suggested as absorption rate characteristics. Several authors have used simulation studies to investigate the relative merits of these characteristics. In contrast, we investigate here the "true" relationships between these four characteristics in a more theoretical manner. Specifically, we show that in the one-compartment open model the difference in tmax, and the ratio of the Cmax/AUC ratio of two drug formulations are equivalent characteristics for the comparison of the absorption rate of two drug formulations. In two- or higher compartment models these relationships hold approximately. This provides a powerful argument for the use of the observed Cmax/AUC ratio, rather than tmax, as a measure for the rate of absorption, because it is well-known that Cmax/AUC can be observed with higher precision than tmax. We also show that the difference in MRT for two-drug formulations equals the difference in mean absorption time under very general conditions, and for the one- and the two-compartmental model we prove this explicitly. Thus the difference in MRT emerges as the most direct characteristic of the difference in absorption rates, and in that sense is superior to both the tmax difference and the Cmax/AUC ratio. Based on empirical evidence and the results of simulation studies published in the literature we recommend that for drugs with short elimination half-lives, the difference in MRT is the primary characteristic for the comparison of absorption rates.(ABSTRACT TRUNCATED AT 250 WORDS)