Bialer M, Yacobi A, Moros D, Levitt B, Houle J M, Munsaka M S
Department of Pharmaceutics and David R. Bloom Centre for Pharmacy, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Epilepsia. 1998 May;39(5):513-9. doi: 10.1111/j.1528-1157.1998.tb01414.x.
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 (Cmax), and time to reach Cmax (tmax), 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), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), t(apical), and C(apical) (the arithmetic mean of the POT times and concentrations within 25% of Cmax, respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve.
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.
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.
The additional parameters examined may supplement the traditional single-point parameters, Cmax and tmax, 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.
人们一直担心，用于确定仿制药生物等效性的标准可能无法充分保证抗癫痫药物（AEDs），特别是控释（CR）制剂的可互换性。除了曲线下面积（AUC）、血浆峰浓度（Cmax）和达峰时间（tmax）外，我们还研究了几个新参数在评估卡马西平（CBZ）及其他CR产品的生物等效性和体内性能方面的应用。这些新参数可能为评估血浆时间-浓度曲线出现显著平台期的CR产品提供额外信息。它们包括平均驻留时间（MRT）、Cmax/AUC、平台期时间或POT（与Cmax的25%范围内的浓度相关的时间跨度）、t(apical)和C(apical)（分别为POT时间和Cmax的25%范围内浓度的算术平均值）。多剂量研究的其他参数包括波动百分比和稳态浓度曲线的平坦度。
这些提议的参数用于最近两项（单剂量和多剂量）CBZ新CR产品（Teril 400 CR）与卡马西平控释片（Tegretol CR Divitab）的双向交叉研究。
通过使用经典参数和提议的额外参数，发现Teril 400 CR与Tegretol CR Divitab具有生物等效性。通过目视检查和提议的参数评估，两种CBZ CR产品具有相似的吸收速率和相似的血浆时间-浓度曲线平坦度。
所研究的额外参数可能补充传统的单点参数Cmax和tmax，用于评估吸收速率和浓度曲线的平坦度。它们的潜在益处和实际效用在这两项研究中得到了证实。鉴于与CBZ治疗相关的浓度依赖性副作用以及CBZ血浆浓度曲线的波动和平坦度对药物疗效和耐受性的影响，吸收速率评估很重要。
