A novel multivariate approach for estimating the degree of similarity in bioavailability between two pharmaceutical...

Statistical assessment of bioavailability and bioequivalence of drug products is generally carried out with a univariate analysis by independently comparing each relevant parameter [such as, area under the drug concentration curve (AUC) and peak drug concentration (Cmax)] of the test and reference products. The assumption is made that AUC and Cmax are independent of each other. In reality, AUC, Cmax, and other pharmacokinetic parameters are dependent on each other. Therefore, a multivariate approach is theoretically superior. In this report, a novel multivariate approach to determine the bioavailability and bioequivalence of pharmaceutical products is described. The method determines the bivariate confidence ellipse (CE) between Cmax and AUC and the trivariate confidence ellipsoid (CED) among Cmax, AUC, and either Tmax or MRT for test and reference products. The similarity between the test and reference products can be assessed by the fraction of overlapping areas of CE and volumes of CED. The method and its comparison with conventional univariate analysis are demonstrated with data obtained from a bioequivalence study of ketoconazole tablets.