Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women

Abstract

The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN‐001 clinical trial, an open label 3‐way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2‐compartment, first‐order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV‐DP by first‐order uptake with first‐order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (Vc) with estimates as follows: absorption rate constant (Ka) 9.79 h−1, absorption lag time 0.5 hours, Vc 385.71–2.16*(73‐WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)*Vc). TFV‐DP's half‐life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN‐001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV‐DP when compared to healthy participant data from another clinical trial.

Population Pharmacokinetics of Tenofovir in HIV-1-Uninfected Members of Serodiscordant Couples and Effect of Dose Reporting Methods

“…Creatinine clearance was a significant covariate of clearance and is biologically meaningful because tenofovir is a renally cleared drug. The population pharmacokinetic parameters are in general agreement with those in previous reports (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…Population pharmacokinetics of tenofovir for HIV-infected patients have been described previously by several authors (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), but none of them used electronic monitoring for adherence. We previously reported population pharmacokinetic models for tenofovir in plasma (15) and for tenofovir in plasma and intracellular tenofovir diphosphate in healthy women (16), with different methods of adherence correction utilizing superposition principles within the model framework. The current study included both men and women and provided an opportunity to test sex as a covariate.…”

“…Several population pharmacokinetic models for tenofovir have been reported (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, all of them include data from HIV-1-infected subjects or a mix of healthy and HIV-infected subjects (7), except for our recent reports on a population of healthy women (15,16). In the current study, patient-reported dosing information (PRDI) was collected in the main trial, and electronic adherence measurements were available in the adherence substudy.…”

Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation

“…Unsurprisingly, given the agreement in plasma PK parameters, the FTC-TP parameters were similar between studies. A limitation of the modeling is that external data sets are required to further evaluate the models; however, it is noteworthy that the TFV-DP and FTC-TP predictions are within the ranges previously reported, including the PrEP population for TFV-DP (15,20,22).…”

“…Given that tenofovir monophosphate and emtricitabine diphosphate concentrations were not measured, this helped limit problems with identifiability of model parameters. A similar model structure has recently been used to describe tenofovir and TFV-DP concentrations in healthy female volunteers (20). An indirect-response model has previously been used to describe plasma tenofovir and IC TFV-DP concentrations in HIV patients (9); however, this model was not supported by our data.…”