Metabolite parameters as an appropriate alternative approach for assessment of bioequivalence of two verapamil formulations.

Abstract

A bioequivalence study of two verapamil formulations (generic verapamil tablets and Isoptin(®) tablets) was performed by comparing pharmacokinetic parameters of the parent drug and its major metabolite, norverapamil following a single dose administration of 80 mg verapamil hydrochloride in 22 healthy volunteers according to a randomized, two-period, crossover-design study. Moreover, the feasibility of proving bioequivalence of verapamil oral dosing form by means of norverapamil pharmacokinetic parameters was evaluated. Concentrations of verapamil and norverapamil were quantified in plasma using a validated high-performance liquid chromatography (HPLC) with fluorescence detection. The 90% CIs for the log-transformed ratios of verapamil Cmax (maximum plasma concentration) and AUC0-∞(area under the plasma concentration-versus-time curve from time zero to the infinity) were 73 to 101 and 80 to 103, respectively. Similarly, the corresponding ranges for norverapamil were 80-100 and 84-103, respectively. According to the parent drug data, the 90% confidence intervals around the geometric mean ratio of AUC happened to fit within preset bioequivalence limits of 80-125%, whereas those for Cmax did not. The 90% confidence intervals for both Cmax and AUC of norverapamil met preset bioequivalence limits. The AUC and Cmax of metabolite, when compared to parent drug, showed a much lower degree of variability and the 90% confidence intervals of the metabolite were therefore narrower than those of the parent drug. These observations indicate that bioequivalence studies using metabolite, norverapamil, could be a more suitable and preferable approach to assess bioequivalence of verapamil formulations due to its much lower variability and therefore lower number of volunteers that are required to conduct the study.