用于预测局部作用的甲硝唑外用乳膏临床性能的体外-体内相关性（IVIVC）
In Vitro-In Vivo Correlations (IVIVC) for Predicting the Clinical Performance of Metronidazole Topical Creams Intended for Local Action.
作者信息
Rath Seeprarani, Kanfer Isadore
机构信息
Biopharmaceutics Research Institute, Rhodes University, Grahamstown 6139, South Africa.
Leslie Dan College of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
出版信息
Pharmaceutics. 2023 Jan 12;15(1):268. doi: 10.3390/pharmaceutics15010268.
The safety and efficacy of a generic medicine can be confirmed by demonstrating bioequivalence (BE) between the generic product and its reference listed drug (RLD) by measuring drug concentrations in the blood following administration. However, for topical dermatological products that are not absorbed into the systemic circulation, clinical trials in patients are required. The objective of this investigation was to use an in vitro method to predict in vivo performance by correlating in vitro release testing (IVRT) data with tape stripping (TS) data following the application of metronidazole (MTZ) creams to the skin of healthy human participants. Whereas IVRT is generally used to characterize the release of a drug from topical products across a synthetic membrane into a suitable receptor medium, TS involves the sequential removal of layers of stratum corneum (SC) with an adhesive tape to determine the amount of the drug in the skin. The resulting IVRT and TS data were correlated using the IVRT parameter of the apparent release constant (ARC), which is the slope obtained from the release rate profile, with the TS parameter of the area under the curve (AUC) obtained from a plot of the amount of drug per tape strip vs. the relative SC depth. A rank order relationship for these parameters was established for the reference and test products. A graph of AUC vs. ARC was plotted to establish a Level C in vitro-in vivo correlation (IVIVC). Although the ARC for T was slightly lower than that for the reference, the rank order was essentially consistent. A linear relationship was observed between the AUCs and ARCs. The equation derived was used to predict the AUCs for all the tested products based on their respective ARCs. The predicted AUC values based on the observed ARCs were similar to the observed AUCs. The lower and upper limits for the in vitro and in vivo parameters for BE were computed based on regulatory acceptance criteria. In order to predict BE from the IVRT studies, the values of the ARC should be between 30.50 and 47.67 when comparing test and reference cream products containing MTZ.
通过给药后测量血液中的药物浓度来证明仿制药与其参比上市药品（RLD）之间的生物等效性（BE），可以确认仿制药的安全性和有效性。然而，对于未被全身循环吸收的局部皮肤科产品，需要在患者中进行临床试验。本研究的目的是使用体外方法，通过将甲硝唑（MTZ）乳膏应用于健康人类受试者皮肤后，将体外释放测试（IVRT）数据与胶带剥离（TS）数据相关联，来预测体内性能。虽然IVRT通常用于表征药物从局部产品通过合成膜释放到合适的受体介质中的情况，但TS涉及用胶带依次去除角质层（SC）的各层，以确定皮肤中的药物量。使用表观释放常数（ARC）的IVRT参数（即从释放速率曲线获得的斜率）与从每条胶带的药物量与相对SC深度的关系图中获得的曲线下面积（AUC）的TS参数，将得到的IVRT和TS数据进行关联。为参比产品和受试产品建立了这些参数的排序关系。绘制AUC与ARC的关系图以建立C级体外-体内相关性（IVIVC）。虽然受试产品的ARC略低于参比产品，但排序基本一致。观察到AUC与ARC之间存在线性关系。所推导的方程用于根据各自的ARC预测所有受试产品的AUC。基于观察到的ARC预测的AUC值与观察到的AUC值相似。根据监管接受标准计算了BE的体外和体内参数的下限和上限。为了从IVRT研究中预测BE，当比较含MTZ的受试乳膏产品和参比乳膏产品时，ARC值应在30.50至47.67之间。
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