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

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.