Cottrell Mackenzie L, Yang Kuo H, Prince Heather M A, Sykes Craig, White Nicole, Malone Stephanie, Dellon Evan S, Madanick Ryan D, Shaheen Nicholas J, Hudgens Michael G, Wulff Jacob, Patterson Kristine B, Nelson Julie A E, Kashuba Angela D M
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina-Chapel Hill.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, employee at the time the work was done.
J Infect Dis. 2016 Jul 1;214(1):55-64. doi: 10.1093/infdis/jiw077. Epub 2016 Feb 24.
A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP).
A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4(+) T cells were used to identify 90% effective concentration (EC90) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues.
The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7-11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue.
This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.
通过将体外疗效靶点与黏膜组织药代动力学（PK）数据及数学模型相结合，开展了一项新型转化药理学研究，以确定有效的人类免疫缺陷病毒（HIV）暴露前预防（PrEP）所需的剂量数。
通过测量47名健康女性黏膜组织中替诺福韦、恩曲他滨、它们的活性代谢产物（分别为替诺福韦二磷酸酯[TFVdp]和恩曲他滨三磷酸酯[FTCtp]）以及竞争性内源性核苷酸（dATP和dCTP）的浓度，建立了PK/药效学（PD）模型。使用TZM-bl细胞和CD4(+) T细胞来确定TFVdp与dATP以及FTCtp与dCTP（单独及联合）对预防HIV的90%有效浓度（EC90）比值。然后进行蒙特卡洛模拟，以确定保护女性下生殖道和直肠组织的最低有效给药策略。
直肠TFVdp浓度比女性下生殖道中的浓度高10倍，而内源性核苷酸的浓度则低7 - 11倍。我们的模型预测，≥98%的人群在每日第三次服用富马酸替诺福韦二吡呋酯加恩曲他滨时可实现保护性黏膜组织暴露。然而，要保护女性下生殖道组织免受HIV感染，每周至少需要坚持服用7剂中的6剂（85%），而保护直肠组织则需要每周坚持服用7剂中的2剂（28%）。
该模型可预测近期PrEP试验结果，即每周2 - 3剂对男性的有效性为75% - 90%，但对女性无效。这些数据为未来的PrEP研究提供了一种新方法，可优化临床试验给药策略。
