LAUSR

Drug-combination nanoparticles (DcNP) is a nano-formulation of multiple HIV drugs in one injectable. DcNP demonstrated long-acting pharmacokinetics (PK) for all drugs in the blood and lymphatic system of nonhuman primates (NHP). Long-acting is due to stably circulating DcNP and a depot in the lymphatic system during subcutaneous absorption. Because the PK of each drug in DcNP evolves through two species, i.e., drugs that dissociate from DcNP and drugs retained in DcNP (Part 2, presented separately), we describe here a physiologically based PK model of the nanoparticle-free drugs featuring the role of the lymphatic system. The free drug model was built using subcutaneous injections of suspended lopinavir-ritonavir-tenofovir in NHP and validated by external experiments. The model, for the first time, introduces the lymphatic network as part of a whole-body PBPK system and singles out major lymphatic regions: cervical, axillary, hilar, mesenteric, and inguinal nodes. Although the scope of the free-drug modeling was to support the construction of the nanoparticle model (Part 2), such a detailed/regionalized description of the lymphatic system and mononuclear cells represent 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 level.