Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

Abstract

Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir‐diphosphate and emtricitabine‐triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir‐diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip‐flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF‐derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract.

Population pharmacokinetics of tenofovir, emtricitabine and intracellular metabolites in transgender women

“…Plasma FTC was best described as a 2‐compartment model with first order absorption and elimination. PK parameter estimates are in general agreement with previous reports 17–19,28,32 . Saturable functions for metabolite formation were not used, given only 1 dose level.…”

A multicompartment population PK model to predict tenofovir and emtricitabine mucosal tissue concentrations for HIV prevention

“…In peripheral blood mononuclear cells (PBMCs), which can be obtained more frequently and are far more accessible than tissue biopsies, metabolite concentrations also vary considerably, at least partially due to complexities in cell isolation and analytical methods. We and others have observed pcVPCs in PBMC models similar to those seen here for tissues 8,15,30,31 …”

“…We and others have observed pcVPCs in PBMC models similar to those seen here for tissues. 8,15,30,31 We do not have bootstrap results of parameter precision estimates due to the excessively long model run time. Even with parallelization across 24 CPUs on our Linux cluster, the model took over a week to converge; therefore a 100 replicate bootstrap would take 2 years to complete.…”

A Novel Algorithm to Improve PrEP Adherence Monitoring Using Dried Blood Spots

“…For both TFVdp and FTCtp, a one-compartment model with first-order absorption and first-order elimination was selected as the base model; this is consistent with other population models of TFVdp and FTCtp when co-modeled with the parent drug. 8,[25][26][27] When examining the covariates of interest described in the Methods section, we did not find that covariates significantly improved model performance for either TFVdp or FTCtp. Therefore, simulations and applications hereafter utilized the base final model (i.e., no covariates).…”