Lin Ho-Pi, Sun Dajun, Zhang Xinyuan, Wen Hong
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
J Pharm Sci. 2016 Oct;105(10):3088-3096. doi: 10.1016/j.xphs.2016.06.015. Epub 2016 Jul 19.
A Food and Drug Administration-approved generic oral product of venlafaxine hydrochloride (HCl) extended-release (ER) tablets has used a release mechanism based on an openable matrix, which is different from the push-pull osmotic pump system of its reference-listed drug. In an extreme case, a delay in the bursting of the openable matrix may be considered a product failure mode that alters the intended profile of systemic exposure. A physiologically based pharmacokinetic absorption model was established and verified to simulate the pharmacokinetic profiles after a single-dose oral administration of ER venlafaxine HCl tablets based on an osmotic pump or openable matrix design. This model adequately predicted the observed human mean pharmacokinetic metrics with <20% difference between the predicted and observed data. Based on the modeling and simulation results, Cmax and AUCt of the venlafaxine openable matrix tablets were entirely within the bioequivalence acceptance limits (i.e., 80%-125%) when the lag time varied from 0 to 4 h and using drug-release profiles under most dissolution conditions. The results indicated that a bioinequivalence risk is minimal for a delayed onset of drug release from the approved generic venlafaxine HCl ER tablets with an openable matrix design, supporting its substitutability to the reference product.
一种经美国食品药品监督管理局批准的盐酸文拉法辛缓释（ER）片的仿制药口服产品采用了基于可开启基质的释放机制，这与其参比制剂的推拉渗透泵系统不同。在极端情况下，可开启基质破裂延迟可被视为一种产品失效模式，会改变预期的全身暴露曲线。建立并验证了一个基于生理的药代动力学吸收模型，以模拟基于渗透泵或可开启基质设计的盐酸文拉法辛缓释片单剂量口服给药后的药代动力学曲线。该模型充分预测了观察到的人体平均药代动力学指标，预测数据与观察数据之间的差异<20%。基于建模和模拟结果，当滞后时间从0到4小时变化且使用大多数溶出条件下的药物释放曲线时，文拉法辛可开启基质片的Cmax和AUCt完全在生物等效性接受限度内（即80%-125%）。结果表明，对于采用可开启基质设计的已批准盐酸文拉法辛缓释仿制药，药物释放延迟导致生物不等效的风险极小，这支持了其与参比产品的可替代性。
