Laboratory of Biopharmaceutics & Pharmacokinetics, Faculty of Pharmacy, National & Kapodistrian University of Athens, 15771, Athens, Greece.
CNS Drugs. 2014 Jan;28(1):69-77. doi: 10.1007/s40263-013-0112-8.
Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics.
The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products.
Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs.
The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types.
Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another.
Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient's status from seizure-free to refractory.
抗癫痫药物（AED）的仿制药目前是一个有争议的话题，因为神经科医生和患者不愿意从品牌产品转换为仿制药，也不愿意在仿制药之间转换。
本研究旨在为 AED 产品的生物等效性（BE）和可互换性问题提供启示。
对经典的 2×2 BE 研究进行了蒙特卡罗模拟，以研究样本量、个体内变异性以及比较产品的药代动力学值的真实差异对仿制药 AED 产品 BE 接受度的影响。模拟扩展到研究两种仿制药产品与同一创新产品的比较性能。将模拟结果与 AED 的文献数据进行比较。
BA 的问题是两种制剂是否不同，而对于 BE，问题是两种制剂在吸收程度和速度方面是否足够相似。因此，BA 和 BE 的标准以及它们分析中涉及的统计分析是不同的。两种符合仿制药监管批准要求的仿制药制剂，即与同一种创新 AED 具有生物等效性，它们可能彼此不具有生物等效性，因此不应被视为相同或具有治疗等效性的产品。从标准或速释制剂转换为改良释放产品，包括延长释放或延迟释放制剂，不应被视为仿制药之间的转换，而应被视为不同制剂类型之间的转换。
从生物等效的仿制药 AED 产品之间的转换可能会导致血浆水平和暴露量发生比品牌到仿制药的转换更大的变化。模拟工作验证了临床发现，即并非所有与同一创新产品生物等效的仿制药 AED 产品彼此生物等效。
两种符合仿制药监管批准要求的仿制药制剂，通过与创新 AED 具有生物等效性，可能彼此不具有生物等效性。需要额外的 BE 标准来进行制剂转换，特别是在癫痫中，突破性发作可能会使患者的状态从无癫痫发作转变为难治性。
