University of North Carolina (UNC), UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
SK Life Science, Inc, Fair Lawn, New Jersey, USA.
Clin Pharmacol Ther. 2019 Oct;106(4):821-830. doi: 10.1002/cpt.1464. Epub 2019 May 31.
Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir-diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip-flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF-derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract.
了解男性生殖道（一个独特的病毒隔室）中的抗逆转录病毒处置情况，可以为 HIV 的根除提供深入了解。进行了群体药代动力学建模，以研究富马酸替诺福韦二吡呋酯（TDF）、替诺福韦艾拉酚胺（TAF）和恩曲他滨及其代谢物在血液和精液中的处置情况。测量了替诺福韦和恩曲他滨在血浆和精液中的浓度，以及外周血单核细胞（PBMC）和精单核细胞中替诺福韦二磷酸和恩曲他滨三磷酸的浓度。顺序隔室建模描述了药物在血液和精液中的处置情况。我们的模型表明，与 TDF 相比，TAF 给药后 PBMC 中表观替诺福韦二磷酸的消除更慢，而 SP 中替诺福韦的消除更快，这可能反映了翻转动力学。此外，与血液相比，TAF 在精液中的代谢似乎更慢；然而，SP 中 TAF 衍生的替诺福韦的消除速度似乎快于其血浆消除速度。这些发现为进一步研究男性生殖道中的细胞进入和药物代谢的机制提供了有价值的见解。
