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

• Published in: Journal of pharmaceutical sciences 2022-02, Vol.111 (2), p.529-541
• Main Authors: Perazzolo, Simone, Shireman, Laura M., Shen, Danny D., Ho, Rodney J.Y.
• Format: Article
• Language: English
• Subjects: Animals; HIV; HIV Infections - drug therapy; Lopinavir; Lymphatic System; Lymphatic transport; Nanoparticle; Nanoparticle delivery; Nonhuman primates; PBPK; Ritonavir; Subcutaneous pharmacokinetics; Tenofovir
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2021.10.007

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.