Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo Road 172, Changsha, 410013, China.
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.
AAPS J. 2024 Jul 3;26(4):77. doi: 10.1208/s12248-024-00951-5.
Dose-scale pharmacodynamic bioequivalence is recommended for evaluating the consistency of generic and innovator formulations of certain locally acting drugs, such as orlistat. This study aimed to investigate the standard methodology for sample size determination and the impact of study design on dose-scale pharmacodynamic bioequivalence using orlistat as the model drug. A population pharmacodynamic model of orlistat was developed using NONMEM 7.5.1 and utilized for subsequent simulations. Three different study designs were evaluated across various predefined relative bioavailability ratios of test/reference (T/R) formulations. These designs included Study Design 1 (2×1 crossover with T1 60 mg, R1 60 mg, and R2 120 mg), Study Design 2 (2×1 crossover with T2 120 mg, R1 60 mg, and R2 120 mg), and Study Design 3 (2×2 crossover with T1 60 mg, T2 120 mg, R1 60 mg, and R2 120 mg). Sample sizes were determined using a stochastic simulation and estimation approach. Under the same T/R ratio and power, Study Design 3 required the minimum sample size for bioequivalence, followed by Study Design 1, while Study Design 2 performed the worst. For Study Designs 1 and 3, a larger sample size was needed on the T/R ratio < 1.0 side for the same power compared to that on the T/R ratio > 1.0 side. The opposite asymmetry was observed for Study Design 2. We demonstrated that Study Design 3 is most effective for reducing the sample size for orlistat bioequivalence studies, and the impact of T/R ratio on sample size shows asymmetry.
推荐采用剂量比例药效生物等效性来评估某些局部作用药物（如奥利司他）的仿制药与原研药制剂的一致性。本研究旨在探讨使用奥利司他作为模型药物时，用于确定样本量的标准方法以及研究设计对剂量比例药效生物等效性的影响。采用 NONMEM 7.5.1 开发了奥利司他的群体药效动力学模型，并用于随后的模拟。评估了三种不同的研究设计，这些设计涵盖了各种预设的受试制剂/参比制剂（T/R）相对生物利用度比值。这些设计包括：研究设计 1（2×1 交叉设计，T1 为 60mg，R1 为 60mg，R2 为 120mg）、研究设计 2（2×1 交叉设计，T2 为 120mg，R1 为 60mg，R2 为 120mg）和研究设计 3（2×2 交叉设计，T1 为 60mg，T2 为 120mg，R1 为 60mg，R2 为 120mg）。采用随机模拟和估计方法确定样本量。在相同的 T/R 比值和功效下，研究设计 3 需要最小的样本量即可达到生物等效性，其次是研究设计 1，而研究设计 2 的效果最差。对于研究设计 1 和 3，在相同功效下，对于 T/R 比值<1.0 的一侧，需要比 T/R 比值>1.0 的一侧更大的样本量。对于研究设计 2，观察到相反的不对称性。我们表明，研究设计 3 最有效地减少奥利司他生物等效性研究的样本量，并且 T/R 比值对样本量的影响表现出不对称性。
