Population pharmacokinetics and exposure‐response relationship for temsavir following fostemsavir administration in treatment‐experienced <scp>HIV</scp> patients

Fostemsavir (FTR, GSK3684934; formerly BMS-663068) is a human immunodeficiency virus type 1 (HIV-1) attachment inhibitor approved for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced (HTE) patients failing their current antiretroviral regimen. FTR is an extended-release prodrug and is hydrolyzed by alkaline phosphatase in the gastrointestinal lumen to its active moiety, temsavir (TMR). TMR is primarily metabolized by esterase-mediated hydrolysis with contributions from cytochrome P450 (CYP) 3A4. A population pharmacokinetic (PK) analysis was performed using TMR exposure data from seven clinical studies (Phases 1 through 3) to characterize the time course of TMR plasma concentrations and to evaluate covariate effects on TMR PK. This analysis showed TMR PK was adequately described using a two-compartment model with dual zero and first-order absorption and first-order elimination with CYP3A inducers and inhibitors as covariates on CL/F and allometrically scaled body weight as a covariate on CL/F, V2/F, Q/F, and V3/F. Exposure metrics were derived from the final population PK model to assess relationships between TMR PK and efficacy at Day 8 and Week 24 and safety endpoints of interest, using exposure-response (ER) models. Both the population PK and E-R models support administration of FTR 600 mg BID to decrease virologic load in HIV-1 HTE patients, with no dose adjustments necessary for coadministration with moderate CYP3A inducers, strong CYP3A inhibitors, prandial status, or body weight. Results from this analysis supported the regulatory approval of the fostemsavir 600 mg dose and are applicable to clinical trial simulations in other scenarios and populations (e.g., pediatrics).