Pharmacokinetics of Temsavir, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug, Fostemsavir, Coadministered with Cobicistat, Etravirine, Darunavir/Cobicistat, or Darunavir/Ritonavir with or without Etravirine in Healthy Participants

Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4(+) T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes. Drugs that induce or inhibit CYP3A, P-glycoprotein, and BCRP may affect temsavir concentrations. Understanding potential drug-drug interactions (DDIs) following fostemsavir coadministration with antiretrovirals approved for HIV-1-infected treatment-experienced patients, including darunavir plus cobicistat (DRV/c) or DRV plus low-dose ritonavir (DRV/r) and etravirine, is clinically relevant. Open-label, single-sequence, multiple-dose, multicohort DDI studies were conducted in healthy participants (n = 46; n = 32). The primary objective was to assess the effects of DRV/r, etravirine, DRV/r plus etravirine, cobicistat, and DRV/c on temsavir systemic exposures; safety was a secondary objective. Compared with fostemsavir alone, coadministration with DRV/r increased the temsavir maximum observed plasma concentration (C-max), area under the concentration-time curve in one dosing interval (AUC(tau)), and plasma trough concentration (C-tau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir C-max, AUC(tau), and C-tau by similar to 50% each. DRV/r plus etravirine increased the temsavir C-max, AUC(tau), and C-tau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir C-max, AUC(tau), and C-tau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir C-max, AUC(tau), and C-tau by 79%, 97%, and 124%, respectively. Fostemsavir with all combinations was generally well tolerated. No dose adjustment is required for fostemsavir when coadministered with strong CYP3A inhibitors, P-glycoprotein inhibitors, and modest inducers, including regimens with DRV/r, DRV/c, cobicistat, etravirine, and DRV/r plus etravirine based on the therapeutic margin for temsavir.

Automated summary

Fostemsavir is a new drug that effectively prevents HIV-1 from entering host cells. Its metabolism is influenced by certain enzymes, and coadministration with other drugs may affect its concentration. This study evaluates the impact of combining fostemsavir with different antiretroviral drugs, showing that some combinations increase temsavir concentrations while others decrease them. Overall, fostemsavir is well tolerated in various combination regimens and does not require dosage adjustments.