A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system.

ABSTRACT

The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category. A small variation in the number of subjects was constantly observed in bioequivalence studies using dosage forms containing an identical BCS class 1 or class 3 drug, even though formulations of the generic product differ between companies. The variation was extremely enlarged when the drugs were substituted with BCS class 2 drugs. Rate-determining steps in oral absorption of highly water-soluble BCS class 1 and class 3 drugs are independent of formulations when there is no significant difference in the in vitro dissolution profiles between formulations. The small variation observed for both BCS categories indicates that the number of subjects converges into one value for each drug. Our analysis indicates the appropriateness of biowaiver of bioequivalence studies for immediate-release solid oral dosage forms containing not only BCS class 1 drugs but also class 3 drugs.