Intracellular Tenofovir and Emtricitabine Anabolites in Genital, Rectal, and Blood Compartments from First Dose to Steady State

Abstract

The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2-10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5-1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/10⁶ cells, 898-2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/10⁶ cells, 85-106), seminal cells (22 fmol/10⁶ cells, 6-79), and cervical cells (111 fmol/10⁶ cells, 64-194). FTC-TP Css was highest in PBMC (5.7 pmol/10⁶ cells, 5.2-6.1) and cervical cells (7 pmol/10⁶ cells, 2-19) versus rectal (0.8 pmol/10⁶ cells, 0.6-1.1) and seminal cells (0.3 pmol/10⁶ cells, 0.2-0.5). Genital drug concentrations on days 1-7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14⁺ compared with CD4⁺, CD8⁺, and CD19⁺ cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.

Keywords: HIV pre-exposure prophylaxis; genital compartment; intracellular; nucleoside analog; pharmacokinetics; rectal compartment.

FIG. 1.

Genital fluid TFV and FTC concentration–time curves stratified by sex. All available CVF and seminal fluid data, with the exception of TFV in CVF, from female and male participants, respectively, were ln transformed before fitting with a one-phase exponential association model; Ct = Css × (1 − e^{−K × t}), where Ct is the averaged drug concentration at time t, Css is the fitted steady-state drug concentration, and K is the fitted first-order elimination rate constant. Css and corresponding 95% confidence intervals are shown for each graph. Css, steady-state concentration; CVF, cervicovaginal fluid; FTC, emtricitabine; TFV, tenofovir.

FIG. 2.

Css of TFV-DP and FTC-TP in PBMC at day 1 and 30 stratified by HIV serostatus. The noncompartmental analysis Css results from day 1 to 30 were plotted and connected per participant. The geometric mean and 95% confidence intervals for Css values are shown for each time point. FTC-TP, emtricitabine-triphosphate; PBMC, peripheral blood mononuclear cells; TFV-DP, tenofovir-diphosphate.

FIG. 3.

Cervical cell and seminal mononuclear cell TFV-DP and FTC-TP concentration–time curves stratified by sex. TFV-DP and FTC-TP data were ln transformed before fitting with a one-phase exponential association model (similar to Fig. 1). Css and corresponding 95% confidence intervals are shown for each graph.

FIG. 4.

Rectal mononuclear cell concentration–time curves for TFV-DP and FTC-TP. TFV-DP and FTC-TP data were ln transformed before fitting with a one-phase exponential association model (similar to Fig. 1). Css and corresponding 95% confidence intervals are shown for each graph.