Development of a Semi-Mechanistic Population Pharmacokinetic Model for Predicting Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Exposure in Plasma and Cellular Matrices During Pregnancy and Postpartum
Year: 2025
Type: article
Abstract: BACKGROUND AND OBJECTIVE: Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind observed differences between dried blood spots and PBMCs remain unclear. METHODS: To address this gap, we developed a semi-mechanistic model to simultaneously describe the pharmacokinetics of all clinically relevant TDF and TAF-derived moieties and conducted clinical trial simulations to compare TDF and TAF pharmacokinetics during pregnancy and postpartum. RESULTS: The pharmacokinetics of plasma TAF and TFV were best described by one-compartment and two-compartment models, respectively, with first-order absorption. A transit compartment was included to reflect the slower elimination rate of plasma TFV after receiving TAF. Cellular matrix PBMC and dried blood spots were included using a biophase model. For TDF, plasma TFV apparent clearance increased by 24.9% and 13.1% during the second and third trimesters of pregnancy, respectively, compared with non-pregnant populations. In the postpartum period, plasma TFV apparent clearance in pregnant women was 9.3% lower than in non-pregnant women. The bioavailability for TAF decreased by 17.3% and 5.1% during the second and third trimesters, respectively, and increased by 18% during the postpartum period relative to non-pregnant women. In pregnant women, simulations showed that TAF maintains approximately five times higher tenofovir diphosphate concentrations in PBMCs compared with TDF during the second and third trimesters, despite a decrease in PBMC tenofovir diphosphate concentrations for both drugs. This finding is consistent with the higher PBMC loading effect of TAF observed in non-pregnant populations. CONCLUSIONS: Our semi-mechanistic model provides a framework for understanding pregnancy-associated pharmacokinetic changes and supports future research to refine dosing strategies for HIV treatment and prevention in pregnancy.
Source: Clinical Pharmacokinetics
Institutions: University at Buffalo, State University of New York, University of Colorado Anschutz, Eastern Virginia Medical School, Old Dominion University, University of California San Diego, Rady Children's Hospital-San Diego, Johns Hopkins University, Boston University, University of Cape Town, University of Washington, University of Alabama at Birmingham, University of California, Los Angeles, MedStar Washington Hospital Center, Georgetown University, MedStar Health Research Institute
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: United States Agency for International Development, U.S. President’s Emergency Plan for AIDS Relief, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Placental Microvasculature in Pregnancies Complicated by HIV, Novel approaches for quantitative assessment of adherence, PrEP and ART adherence monitoring using dried blood spots, COMPLETION OF PHASE III CLINICAL TRIAL, NEW DRUG APPLICATION DOSSIER, AND IMPLEMENTATION STUDIES FOR TENOFOVIR 1% GEL, A FIRST-IN-CLASS TOPICAL PROD, G3733170880, G7575979767, SDMC - IMPAACT Leadership Group, International Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network, The University of North Carolina Center for AIDS Research, IMPAACT Leadership Group
OpenAlex ID: W4416144602