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Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial.

ABSTRACT: OBJECTIVE:VIOLIN (TMC125IFD3002; NCT01422330) evaluated the safety, tolerability, and pharmacokinetics of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected patients. METHODS:In a 48-week, phase IV, single-arm, multicenter study, patients on prior antiretroviral therapy (?8?weeks) who needed to change regimen for virologic failure (viral load???500?copies/mL) or simplification/adverse events (viral load?

SUBMITTER: Arathoon E

PROVIDER: S-EPMC5367767 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial.

Arathoon Eduardo E Bhorat Asad A Silaghi Rodica R Crauwels Herta H Lavreys Ludo L Tambuyzer Lotke L Van Baelen Ben B Vanveggel Simon S Opsomer Magda M

SAGE open medicine 20170118

<h4>Objective</h4>VIOLIN (TMC125IFD3002; NCT01422330) evaluated the safety, tolerability, and pharmacokinetics of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected patients.<h4>Methods</h4>In a 48-week, phase IV, single-arm, multicenter study, patients on prior antiretroviral therapy (⩾8 weeks) who needed to change regimen for virologic failure (viral load ⩾ 500 copies/mL) or simplification/adverse events (viral load < 50 copies/mL) received etravirine 200 mg bid w ...[more]

PMID: 28382208

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Project description: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).

Dataset Information

Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial.

Publications

Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial.

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