Tenofovir Plasma Concentration from Preexposure Prophylaxis at the Time of Potential HIV Exposure: a Population Pharmacokinetic Modeling and Simulation Study Involving Serodiscordant Couples in East Africa

Abstract

The Partners Demonstration Project was a prospective, open-label, implementation science-driven study of preexposure prophylaxis (PrEP) among heterosexual HIV serodiscordant couples in Kenya and Uganda. Adherence data were collected using the Medication Event Monitoring System (MEMS), and time of sexual activity was collected using the mobile phone short message service (SMS). Two plasma samples were collected at a single study visit. We integrated adherence, pharmacokinetics, and SMS data using a population pharmacokinetic (PopPK) model to simulate tenofovir plasma concentrations from PrEP at the time of sexual activity. In the first stage of this analysis, we used data from the current study to update a prior PopPK model of tenofovir (TFV) developed with data from the Partners PrEP Study (a phase III clinical trial). The second stage involved simulating plasma concentrations at the time of sexual activity using empirical Bayes estimates (EBEs) derived from the final model. In addition, EBEs from a previously published parent metabolite model of TFV (MTN-001, an open-label 3-way crossover study in healthy women) was used to simulate tenofovir diphosphate (TFV-DP) concentrations. We estimated percent PrEP "coverage" as the number of reported sexual events during which simulated concentrations were above an a priori threshold concentrations associated with a high degree of protection from HIV infection: plasma TFV of >40 ng/ml and peripheral blood mononuclear cell (PBMC) TFV-DP concentration of >36 fmol/million cells. The levels of coverage were 72% for TFV and 81% for TFV-DP. These levels are consistent with a high degree of protection against HIV acquisition in this study of a pragmatic delivery model for antiretroviral-based HIV prevention.

Keywords: PrEP; population pharmacokinetics; preexposure prophylaxis; tenofovir.

FIG 1

Two-compartment PopPK model of tenofovir with first-order absorption and lag time (T_lag). CL, V_c, V_p, and Q, clearance, volume of central compartment, volume of peripheral compartment, and intercompartmental clearance, respectively.

FIG 2

Basic goodness-of-fit plots for the developed population pharmacokinetic model. The graph at the top left represents individual predicted and observed concentrations, and the graph at the top right represents population predicted concentrations and observed concentrations. The graph at the bottom left represents time versus conditional weighted residuals, and the graph at the bottom right represents population predicted concentrations versus conditional weighted residuals. None of these plots showed any major bias in the model, suggesting that the developed model is acceptable.

FIG 3

Visual predictive check. The plot illustrates observed concentrations and prediction intervals of VPC. Dashed lines show the 90% prediction interval. The solid line represents median of the predictions. The dots represent the observed concentrations.

FIG 4

Simulated TFV and TFV-DP concentrations during SMS study periods. The plots show the TFV and TFV-DP concentrations above and below a priori threshold values (represented as solid lines parallel to the x axis) during SMS study windows. The thresholds were 40 ng/ml for TFV and 36 fmol/million cells for TFV-DP.

FIG 5

Correlation of BQL versus normalized NTT and CL_CR. The graph on the left shows the correlation between BQL and normalized NTT. The plot showed that the median normalized NTT value in the group with BQL concentrations (1) was significantly higher (P < 0.001) than for the group without BQL concentrations (0). The graph on the right shows the relation between BQL concentration and CL_CR. The plot showed that difference in median values of CL_CR is not significant (P = 0.316) between the group with BQL concentrations (1) and the group without BQL concentrations (0).