Background: Vesatolimod (VES) is an orally administered toll-like receptor 7 (TLR7) agonist under development for HIV cure. It is a substrate of both CYP3A and P-gp and can interact with antiretroviral therapy (ART) regimens and other commonly prescribed medications in people with HIV (PWH). A drug-drug interaction (DDI) study with CYP3A and P-gp modulators will allow VES dose adjustment and guide patient inclusion in future clinical trials. Methods: A PBPK model was developed for VES using physiochemical parameters, in vitro and preclinical data and refined by clinical PK data, in vitro permeability and efflux transporter data. Voriconazole (VOR) PBPK model was developed by published clinical PK data from single and multiple dose studies and a pharmacogenomics study. A cobicistat (COBI) model previously developed in house and a rifabutin (RIF) model from Simcyp compound library were used. Different DDI study designs were simulated to optimize the VES dose regimen for maximum interaction. Dose reduction was simulated to ensure VES exposure with strong inhibitors does not exceed previously established safety range. Results: The model was able to describe the PK profiles of VES in relevant dose range. VOR and COBI models were validated based on their DDI predictions with CYP3A and P-gp substrate. The exposures of VES at 2 mg given with COBI or VOR will be in the range of 6-8 mg with VES given alone. VOR given at 400 mg BID on Day 1 as a loading dose followed by 200 mg BID for 2 days and VES dosing on Day 3, COBI at 150mg QD followed by VES dosing on Day 2, and RIF at 300mg QD followed by VES dosing on Day 6 were regimens proposed to evaluate the maximum DDI potential with VES. Conclusion: PBPK modeling was successfully used to inform DDI study design to maximize the interaction while ensuring safety. VES model will be refined when clinical DDI data become available.
