The Journal of pharmacology and experimental therapeutics 2018 02 23() pii 10.1124/jpet.117.247288
Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 (CYP) activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PI). Plasma drug concentrations in are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug-drug interactions are limited as the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism. Thus, we created a mouse strain with the human PXR, CAR and CYP3A4/7 genes on a NOD.Cg-JicTac background (hCYP3A-NOG) and used them to evaluate the impact of human CYP3A metabolism on ARV pharmacokinetics. In proof of concept studies we used nanoformulated atazanavir (nanoATV) with or without RTV. NOG and hCYP3A-NOG mice were treated weekly with 50 mg/kg nanoATV alone or boosted with nanoRTV (nanoATV/r). Plasma was collected weekly and liver at 28 days post-treatment. Plasma and liver ATV concentrations in nanoATV/r-treated hCYP3A-NOG mice were 2- to 4-fold higher than in replicate NOG mice. RTV enhanced plasma and liver ATV concentrations 3-fold in hCYP3A-NOG mice and 1.7-fold in NOG mice. The results indicate that human CYP3A-mediated drug metabolism is reduced compared to mouse and that RTV differentially affects human gene activity. These differences can affect responses to PIs in humanized mouse models of HIV-1 infection. Importantly, hCYP3A-NOG mice reconstituted with human immune cells can be used for bench to bedside translation.