Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States of America.
Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, U.S. Food and Drug Administration, Silver Spring, MD 20993, United States of America.
J Control Release. 2022 Feb;342:134-147. doi: 10.1016/j.jconrel.2021.11.030. Epub 2021 Nov 25.
The value of developing an in vitro/in vivo correlation (IVIVC) is substantial in biopharmaceutical drug development because once the model is developed and validated, an in vitro method may be used to efficiently assess and predict drug product performance in vivo. In this study, three bioequivalent, matrix-type, fentanyl transdermal delivery systems (TDS) were evaluated in vitro using an in vitro permeation test (IVPT) and dermatomed human skin, and in vivo in human pharmacokinetic (PK) studies under harmonized study designs to evaluate IVIVC. The study designs included 1 h of transient heat application (42 ± 2°C) at either 11 h or 18 h after TDS application to concurrently investigate the influence of heat on drug bioavailability from TDS and the feasibility of IVPT to predict the effects of heat on TDS in vivo. Level A (point-to-point) and Level C (single point) IVIVCs were evaluated by using PK-based mathematical equations and building IVIVC models between in vitro fraction of drug permeation and in vivo fraction of drug absorption. The study results showed that the three differently formulated fentanyl TDS have comparable (p > 0.05) heat effects both in vitro and in vivo. In addition, the predicted steady-state concentration (C) from in vitro flux data and the observed C in vivo showed no significant differences (p > 0.05). However, the effects of heat on enhancement of fentanyl bioavailability observed in vivo were found to be greater compared to those observed in vitro for all three drug products, resulting in a weak prediction of the impact of heat on bioavailability from the in vitro data. The results from the current work suggest that while IVPT can be a useful tool to evaluate the performance of fentanyl TDS in vivo with a relatively good predictability at a normal temperature condition and to compare the effect of heat on drug delivery from differently formulated TDS, additional testing measures would enhance the ability to predict the heat effects in vivo with a lower prediction error.
开发体外-体内相关性（IVIVC）在生物制药药物开发中具有重要意义，因为一旦模型得到开发和验证，就可以使用体外方法来有效地评估和预测药物产品在体内的性能。在这项研究中，使用体外渗透试验（IVPT）和去皮人体皮肤，对三种生物等效的基质型芬太尼透皮给药系统（TDS）进行了体外评估，并在人体药代动力学（PK）研究中进行了体内评估，这些研究采用了协调的研究设计来评估 IVIVC。这些研究设计包括在 TDS 应用后 11 小时或 18 小时应用 1 小时短暂加热（42±2°C），以同时研究加热对 TDS 中药物生物利用度的影响以及 IVPT 预测 TDS 体内加热效果的可行性。使用基于 PK 的数学方程和构建体外药物渗透分数与体内药物吸收分数之间的 IVIVC 模型，对等级 A（点对点）和等级 C（单点）IVIVC 进行了评估。研究结果表明，三种不同配方的芬太尼 TDS 在体外和体内都具有可比较的（p＞0.05）热效应。此外，从体外通量数据预测的稳态浓度（C）与体内观察到的 C 没有显著差异（p＞0.05）。然而，与所有三种药物产品的体外观察结果相比，体内观察到的热对芬太尼生物利用度的增强作用更大，导致体外数据对生物利用度的热影响预测能力较弱。当前工作的结果表明，虽然 IVPT 可以成为一种有用的工具，用于在正常温度条件下评估芬太尼 TDS 的体内性能，并比较不同配方 TDS 中药物传递的热效应，但需要额外的测试措施来提高预测体内热效应的能力，降低预测误差。
