Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles.
Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles.
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DOI：
10.1016/j.xphs.2021.10.009
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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：
我们以前开发了一种基于机制的药代动力学（MBPK）模型，以表征淋巴细胞靶向的长效3种HIV药物组合纳米粒（DcNP）制剂洛匹那韦，利托那韦和替诺福韦的PK。MBPK描述了血浆药物浓度的时间过程，并为DcNP的淋巴PK提供了初步假设。由于MBPK的解剖学和生理学解释是有限的，在第2部分中，我们报告了基于生理学的药代动力学（PBPK）模型的开发，用于详细评估与DcNP相关的药物的全身和淋巴PK。DcNP模型与第1部分中先前提出的PBPK模型相关联，以解释释放的游离药物的处置。DcNP模型的一个关键特征是注射剂量从皮下部位吸收到邻近的淋巴储库，通过淋巴网络内和整个淋巴网络的淋巴结，随后进入血液循环。此外，该模型解释了DcNP通过淋巴循环和单核细胞迁移转运到淋巴。目前的PBPK模型可以扩展到靶向或通过淋巴系统转运的其他纳米药物组合。PBPK模型可以允许缩放和预测人类中的DcNP PK。
We previously developed a mechanism-based pharmacokinetic (MBPK) model to characterize the PK of a lymphocyte-targeted, long-acting 3 HIV drug-combination nanoparticle (DcNP) formulation of lopinavir, ritonavir, and tenofovir. MBPK describes time-courses of plasma drug concentration and has provided an initial hypothesis for the lymphatic PK of DcNP. Because anatomical and physiological interpretation of MBPK is limited, in this Part 2, we report the development of a Physiologically Based Pharmacokinetic (PBPK) model for a detailed evaluation of the systemic and lymphatic PK of drugs associated with DcNP. The DcNP model is linked to the PBPK model presented earlier in Part 1 to account for the disposition of released free drugs. A key feature of the DcNP model is the uptake of the injected dose from the subcutaneous site to the adjacent lymphoid depot, routing through the nodes within and throughout the lymphatic network, and its subsequent passage into the blood circulation. Furthermore, the model accounts for DcNP transport to the lymph by lymphatic recirculation and mononuclear cell migration. The present PBPK model can be extended to other nano-drug combinations that target or transit through the lymphatic system. The PBPK model may allow scaling and prediction of DcNP PK in humans.
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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：
3.8
作者：
Perazzolo S;Zhu L;Lin W;Nguyen A;Ho RJY
通讯作者：
Ho RJY
影响因子：
4.9
作者：
Koehn, Josefin;Ho, Rodney J. Y.
通讯作者：
Ho, Rodney J. Y.
影响因子：
3.8
作者：
McConnachie, Lisa A.;Kinman, Loren M.;Ho, Rodney J. Y.
通讯作者：
Ho, Rodney J. Y.
DOI：
10.1016/j.ijantimicag.2020.106220
发表时间：
2021-01
影响因子：
10.8
作者：
Flexner C;Owen A;Siccardi M;Swindells S
通讯作者：
Swindells S