Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Ann Neurol. 2011 Aug;70(2):221-8. doi: 10.1002/ana.22452. Epub 2011 Jun 29.
Patients with epilepsy are often concerned that switching between brand-name and generic formulations of antiepilepsy drugs (AEDs) may cause clinically significant changes in plasma drug concentrations. We assessed bioequivalence (BE) studies for approved generic AEDs to evaluate US Food and Drug Administration claims that: (1) generic AEDs are accurate copies of reference formulations; (2) delivery of reference formulations may be as variable as generic AEDs and so provide no increased benefit; and (3) switches between generic AED formulations are safe and effective.
We determined differences in 90% confidence interval limits for total drug exposure (AUC(0-t) ) and peak concentration (Cmax) ratios of generic and reference formulations during fasting and fed BE studies. We simulated BE between generic formulations after adjusting for reference values.
AUC(0-t) values of approved reference and generic formulations differed by <15% in 99% of BE studies; Cmax differed by <15% in 89% of studies. Food affected variability of Cmax but not AUC(0-t) . Intersubject variability in Cmax and AUC(0-t) was small and similar for reference and generic products. In simulated switches between 595 pairs of generic AED formulations, estimated AUC(0-t) differed by >15% for 17% of pairs; estimated Cmax differed by >15% for 39%. AEDs with low bioavailability and solubility (eg, oxcarbazepine) had the greatest variability in BE.
Most generic AED products provide total drug delivery (AUC) similar to reference products; differences in peak concentrations between formulations are more common. Switches between generic AED products may cause greater changes in plasma drug concentrations than generic substitutions of reference products.
癫痫患者通常担心抗癫痫药物（AED）的品牌名和仿制药之间的转换可能导致血浆药物浓度发生临床显著变化。我们评估了已批准的仿制药 AED 的生物等效性（BE）研究，以评估美国食品和药物管理局的以下说法：（1）仿制药是参考制剂的准确复制品；（2）参考制剂的递送可能与仿制药一样多变，因此没有增加益处；（3）仿制药制剂之间的转换是安全有效的。
我们在禁食和进食的 BE 研究中确定了仿制药和参考制剂的总药物暴露（AUC（0-t））和峰浓度（Cmax）比值的 90%置信区间限制的差异。我们通过调整参考值来模拟仿制药制剂之间的 BE。
在 99%的 BE 研究中，批准的参考和仿制药制剂的 AUC（0-t）值差异<15%；在 89%的研究中，Cmax 差异<15%。食物会影响 Cmax 的变异性，但不会影响 AUC（0-t）。Cmax 和 AUC（0-t）的个体间变异性较小，参考和仿制药产品相似。在 595 对仿制药 AED 制剂的模拟转换中，估计的 AUC（0-t）差异>15%的比例为 17%；估计的 Cmax 差异>15%的比例为 39%。生物利用度和溶解度低的 AED（如奥卡西平）的 BE 变异性最大。
大多数仿制药 AED 产品提供与参考产品相似的总药物递送（AUC）；制剂之间的峰浓度差异更为常见。仿制药 AED 产品之间的转换可能导致血浆药物浓度的变化大于参考产品的仿制药替代。
