Clinical trial simulation to evaluate tenofovir disoproxil fumarate/emtricitabine HIV pre-exposure prophylaxis dosing during pregnancy

Rachel K Scott; Yifan Yu; Mark A Marzinke; Jenell S Coleman; Craig W Hendrix; Robert Bies

doi:10.3389/frph.2023.1224580

Clinical trial simulation to evaluate tenofovir disoproxil fumarate/emtricitabine HIV pre-exposure prophylaxis dosing during pregnancy

Front Reprod Health. 2023 Sep 27:5:1224580. doi: 10.3389/frph.2023.1224580. eCollection 2023.

Authors

Rachel K Scott^#¹, Yifan Yu^#², Mark A Marzinke³, Jenell S Coleman⁴, Craig W Hendrix³, Robert Bies²

Affiliations

¹ Women's Health Research, MedStar Health Research Institute, Washington, DC, United States.
² Department of Pharmaceutical Sciences, University of Buffalo, Buffalo, NY, United States.
³ Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
⁴ Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

^# Contributed equally.

Abstract

Objective: To evaluate upward-adjustment of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) pre-exposure prophylaxis (PrEP) dosing during pregnancy in order to maintain target plasma concentrations associated with HIV protection.

Design: Population pharmacokinetic (PK) modeling and clinical trial simulation (CTS).

Material and methods: We developed population pharmacokinetic models for TFV and FTC using data from the Partners Demonstration Project and a PK study of TDF/FTC among cisgender women by Coleman et al., and performed an in-silico simulation. Pregnancy-trimester was identified as a significant covariate on apparent clearance in the optimized final model. We simulated 1,000 pregnant individuals starting standard daily oral TDF/FTC (300 mg/200 mg) prior to pregnancy. Upon becoming pregnant, simulated patients were split into two study arms: one continuing standard-dose and the other receiving double standard-dose throughout pregnancy.

Results: Standard-dose trough TFV concentrations were significantly lower in pregnancy compared to pre-pregnancy, with 34.0%, 43.8%, and 65.1% of trough plasma concentrations below the lower bound of expected trough concentrations presumed to be the protective threshold in the 1st, 2nd, and 3rd trimesters, respectively. By comparison, in the simulated double-dose group, 10.7%, 14.4%, and 27.8% of trough concentrations fell below the estimated protective thresholds in the 1st, 2nd, and 3rd trimesters, respectively. The FTC trough plasma concentration during pregnancy was also lower than pre-pregnancy, with 45.2% of the steady-state trough concentrations below the estimated protective trough concentrations of FTC. In the pregnancy-adjusted double-dose group, 24.1% of trough plasma concentrations were lower than protective levels.

Conclusions: Our simulation shows >50% of research participants on standard dosing would have 3rd trimester trough plasma TFV concentrations below levels associated with protection. This simulation provides the quantitative basis for the design of prospective TDF/FTC studies during pregnancy to evaluate the safety and appropriateness of pregnancy-adjusted dosing.

Keywords: HIV infection; clinical trial simulation; emtricitabine; population pharmacokinetic modeling; pre-exposure prophylaxis; pregnancy; tenofovir.

Abstract

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