Physiologically-Based Pharmacokinetic Modeling of Tenofovir Disoproxil Fumarate in Pregnant Women.

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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Citation

Xiqian Zhang, Tao Luo, Huan Yang, Wan Ying Ma, Qin He, Min Xu, Yujie Yang. Physiologically-Based Pharmacokinetic Modeling of Tenofovir Disoproxil Fumarate in Pregnant Women. Current drug metabolism. 2023;23(14):1115-1123

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PMID: 36718061

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