Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application.
Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application.
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使用体外皮肤渗透测试和瞬态热影响下的人体药代动力学研究评估三种芬太尼透皮给药系统的体外/体内相关性。
DOI：
10.1016/j.jconrel.2021.11.030
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Stinchcomb,AudraL
中科院分区：
文献类型：
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作者：
Shin,SooHyeon;Yu,Mingming;Hammell,DanaC;Ghosh,Priyanka;Raney,SamG;Hassan,HazemE;Stinchcomb,AudraL
开发体外/体内相关性（IVIVC）的价值在生物制药药物开发中具有重要意义，因为一旦模型开发和验证，体外方法可用于有效评估和预测制剂的体内性能。在这项研究中，三个生物等效的，矩阵型，芬太尼透皮给药系统（TDS）进行了评价，在体外使用的体外渗透试验（IVPT）和dermatomed人皮肤，并在体内人体药代动力学（PK）研究协调的研究设计，以评估IVIVC。研究设计包括在TDS应用后11小时或18小时短暂加热1小时（42 ± 2°C），以同时研究热对TDS药物生物利用度的影响以及IVPT预测热对TDS体内影响的可行性。通过使用基于PK的数学方程和建立药物体外渗透分数与药物体内吸收分数之间的IVIVC模型，评价A级（点对点）和C级（单点）IVIVC。研究结果表明，三种不同配方的芬太尼TDS在体外和体内的热效应相当（p> 0.05）。此外，从体外通量数据预测的稳态浓度（Css）和体内观察到的Cssin无显著差异（p> 0.05）。然而，发现热对体内观察到的芬太尼生物利用度增强的影响大于体外观察到的所有三种药物产品，导致体外数据中热对生物利用度影响的预测较弱。从目前的工作的结果表明，虽然IVPT可以是一个有用的工具来评估芬太尼TDS在体内的性能，在正常温度条件下具有相对较好的可预测性，并比较热对药物输送的影响，从不同的配方TDS，额外的测试措施将提高预测体内的热效应的能力，具有较低的预测误差。
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 (Css) from in vitro flux data and the observed Cssin 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.