Criteria to assess in vivo performance and bioequivalence of generic controlled-release formulations of carbamazepine

Abstract

Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled-release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (C(max)), and time to reach C(max) (t(max)), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time-concentration curve. They include mean residence time (MRT), C(max)/AUC, plateau time or POT (the time span associated with the concentrations within 25% of C(max)), t(apical), and C(apical) (the arithmetic mean of the POT times and concentrations within 25% of C(max), respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve. Methods: These proposed parameters were used in two recent (single and multiple dose) two-way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time-concentration curves as assessed by visual inspection and the proposed parameters. Conclusions: The additional parameters examined may supplement the traditional single-point parameters, C(max) and t(max), for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption-rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.