Department of Pharmacy, The Third People's Hospital of Chengdu, College of Medicine, Southwest Jiaotong University, Chengdu, China.
Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Curr Drug Metab. 2023;23(14):1115-1123. doi: 10.2174/1389200224666230130093314.
Physiological changes during pregnancy can affect antiretroviral drug processes and further influence drug efficacy and safety. Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict PK in pregnant women. The objective of this study was to establish a PBPK modeling of tenofovir disoproxil fumarate (TDF) in pregnant women, to provide a reference for the clinical use of TDF.
A full PBPK modeling of tenofovir (TFV) and TDF following i.v. and p.o. administration was developed using the simulation software PK-Sim®. The modeling was then extrapolated to pregnant women based on pregnancy- related physiological parameters in Mobi® Simulator. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of PK parameters (Cmax, tmax, AUC0-∞) to evaluate the accuracy of PBPK modeling.
The developed PBPK modeling successfully predicted the TDF disposition in the non-pregnant population, wherein the MFE average and GMFE of all predicted PK parameters were within a 1.5-fold error range, and more than 96.30% of the predicted drug concentration values were within a 2-fold error range of the measured values. After the extrapolation of these models to the third trimester of pregnancy, the scaling anatomy/physiology and hepatic intrinsic clearance made the pregnant population PBPK modeling meet the standard requirement of 0.5 < MFE and GMFE value < 2. It was more appropriate to simulate the in vivo process of low-dose TDF in pregnant women.
The non-pregnant population PBPK modeling of TDF established in our study can be extrapolated to pregnant women. Our study provides a reference for realizing clinical personalized medication for pregnant women.
妊娠期间的生理变化会影响抗逆转录病毒药物的代谢过程，进而影响药物的疗效和安全性。基于生理学的药代动力学（PBPK）模型为预测孕妇的药代动力学提供了一种独特的方法。本研究的目的是建立替诺福韦二吡呋酯（TDF）在孕妇中的 PBPK 模型，为 TDF 的临床应用提供参考。
使用模拟软件 PK-Sim®建立了静脉注射和口服给药后替诺福韦（TFV）和 TDF 的全 PBPK 模型。然后，根据 Mobi®Simulator 中与妊娠相关的生理参数，将模型外推至孕妇。采用平均倍数误差（MFE）和几何平均倍数误差（GMFE）方法比较 PK 参数（Cmax、tmax、AUC0-∞）的预测值和观察值之间的差异，以评估 PBPK 模型的准确性。
所建立的 PBPK 模型成功预测了非妊娠人群中 TDF 的处置情况，其中所有预测 PK 参数的 MFE 平均值和 GMFE 均在 1.5 倍误差范围内，超过 96.30%的预测药物浓度值在实测值的 2 倍误差范围内。将这些模型外推至妊娠晚期后，缩放解剖/生理学和肝内固有清除率使孕妇 PBPK 模型符合 0.5< MFE 和 GMFE 值<2 的标准要求。更适合模拟孕妇中低剂量 TDF 的体内过程。
本研究中建立的 TDF 非妊娠人群 PBPK 模型可外推至孕妇。本研究为实现孕妇临床个体化用药提供了参考。
