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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

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

Author(s): Xiqian Zhang, Tao Luo, Huan Yang, Wan Ying Ma, Qin He, Min Xu and Yujie Yang*

Volume 23, Issue 14, 2022

Published on: 03 February, 2023

Page: [1115 - 1123] Pages: 9

DOI: 10.2174/1389200224666230130093314

Price: $65

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Tenofovir disoproxil fumarate, pregnant women, hepatic intrinsic clearance, PBPK, PK-Sim®, immune deficiency syndrome (AIDS).

Graphical Abstract
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