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 PBMC accumulated 8.6-fold (95% CI: 7.2-10) from first dose to steady-state (Css), versus 1.7-fold (95% CI: 1.5-1.9) for FTC-TP. Css was reached in approximately 11 days and 3 days, respectively. Css values were similar between HIV-negative versus HIV positive individuals. Css TFV-DP in rectal mononuclear cells (1450 fmol/10^6cells, 898-2340) was achieved in 5 days and was >10-times higher than PBMC (95 fmol/10^6cells; 85-106), seminal cells (22 fmol/10^6cells, 6-79) and cervical cells (111 fmol/10^6cells, 64-194). FTC-TP Css was highest in PBMC (5.7 pmol/10^6cells, 5.2-6.1) and cervical cells (7 pmol/10^6cells, 2-19) versus rectal (0.8 pmol/10^6cells, 0.6-1.1) and seminal cells (0.3 pmol/10^6cells, 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.
Intracellular Tenofovir and Emtricitabine anabolites in Genital, Rectal, and Blood Compartments from first dose to steady-state.