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

Abstract

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 (Cmax), area under the concentration-time curve in one dosing interval (AUCtau), and plasma trough concentration (Ctau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir Cmax, AUCtau, and Ctau by ∼50% each. DRV/r plus etravirine increased the temsavir Cmax, AUCtau, and Ctau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir Cmax, AUCtau, and Ctau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir Cmax, AUCtau, and Ctau 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 (ClinicalTrials.gov registration no. NCT02063360 and NCT02277600).

Keywords: BCRP; CYP3A4; P-glycoprotein; antiretroviral agents; drug-drug interaction; exposure; fostemsavir; heavily treatment experienced.

Conflict of interest statement

The authors declare a conflict of interest. K.M., C.L., and P.A. are employees of ViiV Healthcare and may hold stock in GlaxoSmithKline. N.T. and M.M. are employees of GlaxoSmithKline and may hold stock in the company. H.S. was an employee of Bristol-Myers Squibb at the time the study was conducted and may hold stock in the company. B.V. and S.L. are employees of Bristol-Myers Squibb and may hold stock in the company.

Figures

FIG 1

Effect of (A) DRV/r, (B) ETR, and (C) ETR plus DRV/r on the PK parameters of temsavir (206281). BID, twice daily; DRV/r, ritonavir-boosted darunavir; ETR, etravirine; PK, pharmacokinetics.

FIG 2

Effect of (A) DRV/c and (B) COBI alone on the PK parameters of temsavir. BID, twice daily; COBI, cobicistat; DRV, darunavir; PK, pharmacokinetics; QD, once daily.

FIG 3

Effect of DRV plus COBI, COBI alone, DRV/r, ETR, and ETR plus DRV/r on the PK parameters of temsavir. Closed shapes represent adjusted GMRs, and connected bars represent 90% CIs of the adjusted GMRs. AUCtau, area under the concentration-time curve in one dosing interval; C12, concentration at 12 h after the last dose; CI, confidence interval; Cmax, maximum observed plasma concentration; COBI, cobicistat; DRV, darunavir; DRV/r, ritonavir-boosted DRV; ETR, etravirine; GMR, geometric mean ratio; PK, pharmacokinetics.

FIG 4

Study designs for (A) 206281 and (B) 206285. BID, twice daily; COBI, cobicistat; DRV, darunavir; DRV/r, ritonavir-boosted darunavir; ETR, etravirine; WO, washout.