Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
CPT Pharmacometrics Syst Pharmacol. 2021 Mar;10(3):179-187. doi: 10.1002/psp4.12583. Epub 2021 Feb 6.
Defining tissue and plasma-specific prophylactic drug concentrations is central to pre-exposure prophylaxis product development for sexual transmission of HIV-1. Pharmacokinetic (PK) data from study RMP-02/MTN-006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV-1 seronegative adults was used to construct a multicompartment plasma-rectal tissue population PK model for TFV and tenofovir-diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV-1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.
定义组织和血浆中预防性药物的浓度是开发用于预防 HIV-1 性传播的暴露前预防产品的核心。研究 RMP-02/MTN-006 的药代动力学 (PK) 数据比较了单次口服富马酸替诺福韦二吡呋酯与单次和多次直肠给予替诺福韦 (TFV) 凝胶在 HIV-1 血清阴性成人中的应用，用于构建用于 TFV 和替诺福韦二磷酸酯 (TFVdp) 的多隔室血浆-直肠组织群体 PK 模型在血浆和直肠组织中。PK 数据收集在五个基质中：TFV（血浆、直肠组织匀浆）、TFVdp（外周血单核细胞、直肠单核细胞 (MMC)、直肠组织匀浆）。使用描述 HIV-1 感染和复制的体外试验分析物测定的病毒生长隔室和 p24 抗原表达的延迟效应隔室。使用线性 PK/药效学模型，在体外试验分析物中 MMC TFVdp 水平超过 9000 fmol/百万个细胞，可明显抑制病毒复制至 1%。使用 NONMEM 版本 7.4 估算参数。
