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Intracellular Tenofovir and Emtricitabine anabolites in Genital, Rectal, and Blood Compartments from first dose to steady-state.

Intracellular Tenofovir and Emtricitabine anabolites in Genital, Rectal, and Blood Compartments from first dose to steady-state.
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Seifert S, Chen X, Meditz A, Castillo-Mancilla J, Gardner E, Predhomme J, Clayton C, Austin G, Palmer B, Zheng JH, Klein B, Kerr B, Guida LA, Rower C, Rower JE, Kiser J, Bushman LR, MaWhinney S, Anderson PL,


Seifert S, Chen X, Meditz A, Castillo-Mancilla J, Gardner E, Predhomme J, Clayton C, Austin G, Palmer B, Zheng JH, Klein B, Kerr B, Guida LA, Rower C, Rower JE, Kiser J, Bushman LR, MaWhinney S, Anderson PL, (click to view)

Seifert S, Chen X, Meditz A, Castillo-Mancilla J, Gardner E, Predhomme J, Clayton C, Austin G, Palmer B, Zheng JH, Klein B, Kerr B, Guida LA, Rower C, Rower JE, Kiser J, Bushman LR, MaWhinney S, Anderson PL,

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AIDS research and human retroviruses 2016 8 15()

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 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.

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