Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture.
Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture.
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DOI：
10.1016/j.xphs.2021.10.007
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发表时间：
2022-03
影响因子：
3.8
通讯作者：
Ho, Rodney J. Y.
中科院分区：
文献类型：
--
作者：
Perazzolo, Simone;Shireman, Laura M.;Shen, Danny D.;Ho, Rodney J. Y.
关键词：
药物组合纳米颗粒（DcNP）允许在一次注射中配制多种HIV药物。在非人灵长类动物（NHP）中，DcNP中的所有药物都已在血液和淋巴结中表现出长效药代动力学（PK），使其适用于靶向长效抗逆转录病毒治疗（TLC-ART）。为了支持TLC-ART转化为临床，目的是提出一种基于生理学的PK（PBPK）模型工具，以控制影响相当复杂的DcNP-药物PK的机制。两种物质同时影响药物PK：从DcNP中解离的药物（第1部分）和保留在DcNP中的药物（第2部分，单独列出）。在这里，我们描述了PBPK建模的纳米颗粒的药物。无药物模型建立在皮下注射悬浮洛匹那韦，利托那韦和替诺福韦在NHP，并通过外部实验验证。新颖之处在于设计了淋巴网络作为全身PBPK系统的一部分，该系统包括主要淋巴区域：颈淋巴结、腋淋巴结、肺门淋巴结、肠系膜淋巴结和腹股沟淋巴结。淋巴系统和单核细胞的这种详细/区域化描述代表了前所未有的预测水平，使得游离药物模型可扩展到在区域和细胞水平上靶向淋巴系统的其他小药物分子。
Drug-combination nanoparticles (DcNP) allow the formulation of multiple HIV drugs in one injectable. In nonhuman primates (NHP), all drugs in DcNP have demonstrated long-acting pharmacokinetics (PK) in the blood and lymph nodes, rendering it suitable for a Targeted Long-acting Antiretroviral Therapy (TLC-ART). To support the translation of TLC-ART into the clinic, the objective is to present a physiologically based PK (PBPK) model tool to control mechanisms affecting the rather complex DcNP-drug PK. Two species contribute simultaneously to the drug PK: drugs that dissociate from DcNP (Part 1) and drugs retained in DcNP (Part 2, presented separately). Here, we describe the PBPK modeling of the nanoparticle-free drugs. The free-drug model was built on subcutaneous injections of suspended lopinavir, ritonavir, and tenofovir in NHP, and validated by external experiments. A novelty was the design of a lymphatic network as part of a whole-body PBPK system which included major lymphatic regions: the cervical, axillary, hilar, mesenteric, and inguinal nodes. This detailed/regionalized description of the lymphatic system and mononuclear cells represents an unprecedented level of prediction that renders the free-drug model extendible to other small-drug molecules targeting the lymphatic system at both the regional and cellular levels.
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DOI：
10.1097/qad.0000000000001405
发表时间：
2017-03-27
期刊：
AIDS (London, England)
影响因子：
--
作者：
Kraft JC;McConnachie LA;Koehn J;Kinman L;Collins C;Shen DD;Collier AC;Ho RJ
通讯作者：
Ho RJ
影响因子：
2.9
作者：
Choi K;Chang J;Lee MJ;Wang S;In K;Galano-Tan WC;Jun S;Cho K;Hwang YH;Kim SJ;Park W
通讯作者：
Park W
影响因子：
5.2
作者：
Janneh, Omar;Bray, Patrick G.;Khoo, Saye H.
通讯作者：
Khoo, Saye H.
DOI：
10.1073/pnas.92.7.2484
发表时间：
1995-03-28
影响因子：
11.1
作者：
KEMPF, DJ;MARSH, KC;NORBECK, DW
通讯作者：
NORBECK, DW
影响因子：
4.9
作者：
Dahlberg, Annette M.;Kaminskas, Lisa M.;McIntosh, Michelle P.
通讯作者：
McIntosh, Michelle P.