Aim: Fostemsavir (FTR), an extended-release prodrug of temsavir (TMR), 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 current antiretroviral treatment. A population PK and exposure-response analysis was performed to assess the influence of intrinsic/extrinsic factors and support regulatory approval of 600 mg BID fostemsavir regimen. Methods: Analysis was conducted using TMR data from seven clinical studies (Phases 1-3). Models were assessed using standard goodness of fit and parameter precision (root mean square error (%RSE)). Model-estimated exposure metrics were used to assess TMR PK- efficacy and safety exposure response relationships. Results: TMR PK was adequately described using a two-compartment model with zero and first-order absorption and first-order elimination. Clearance, volume and absorption parameters were precisely estimated (CL/F 51.0 L/hr (2.1% RSE), V2/F 257 1/hr (3.18 %RSE), Ka 2.33 1/hr (13.3 %RSE)). Concomitant CYP3A inducers and inhibitors were covariates on CL/F, and body weight was a covariate on CL/F, V2/F, Q/F, and V3/F. An Emax model described the trough TMR concentration (Ctau) - day 8 plasma HIV-1 RNA relationship (Emax 1.00 log10 c/mL (17.1 %RSE), EC50 64.3 ng/mL (98% RSE)). No exposure-safety relationships were evident. Simulation showed virologic response was achieved irrespective of coadministration with moderate CYP3A inducers, strong CYP3A inhibitors, changes in prandial status, or body weight. Conclusion: Results support administration of FTR 600 mg BID to decrease virologic load in HIV-1 HTE patients, with no dose adjustments necessary for intrinsic or extrinsic factors.