Investigation of the discriminatory ability of analytes for the bioequivalence assessment of ezetimibe: Parent drug, metabolite, total form, and combination of parent drug and total form

The analysis of parent drug is usually the design of choice for a bioequivalence (BE) study. However, there is a controversy regarding the choice of analytes between EMA and USFDA for the BE study of ezetimibe (EZE). The EMA recommends measuring the total form alone, that means the sum of the concentration of “parent” EZE and “metabolite” ezetimibe-glucuronide (EZEG), as the BE determination. On the other hand, the USFDA recommends measuring not only total form but also EZE. The aim of this study was to employ a simulation approach to determine which analyte (e.g., EZE alone, EZEG alone, total form alone, or combination of EZE and total form) was more appropriate for use as a BE indicator. The previously published pharmacokinetic model of EZE and EZEG with enterohepatic circulation was used to generate virtual BE studies. Eight different scenarios were performed with changes in the rate of absorption of EZE and EZEG. Five hundred virtual BE studies were generated for each scenario. In addition, the discriminatory ability of selected analytes for detecting differences in the rate of absorption of EZE and EZEG was evaluated based on power curve performance. The results obtained through simulations indicated that none of the single analytes (EZE alone, EZEG alone, and total form alone) could have clear advantages in terms of discriminatory ability. Therefore, it was recommended that a combination of EZE and total form should be used in the BE assessment.