title: Pharmacokinetics and short-term safety of etravirine in combination with fluconazole or voriconazole in HIV-negative volunteers.
abstract: The nonnucleoside reverse transcriptase inhibitor etravirine, approved for use in treatment-experienced, HIV-1-infected patients, is a substrate and inducer of cytochrome P450 (CYP) 3A4 and a substrate and inhibitor of CYP2C9/CYP2C19. Pharmacokinetic interactions and safety of etravirine 200 mg twice daily coadministered with fluconazole 200 mg daily or voriconazole 200 mg twice daily, both inhibitors of CYP3A4, CYP2C9, and CYP2C19, were evaluated in an open-label, randomized, 3-period crossover trial in 18 HIV-negative volunteers. Based on least squares means (LSM) ratios, coadministration of etravirine with fluconazole or voriconazole resulted in higher etravirine exposures (area under plasma concentration-time curve from 0-12 hours [AUC(12)             (h) ] 1.86- and 1.36-fold, respectively). Fluconazole pharmacokinetics were unchanged with etravirine coadministration (AUC(12)             (h)  LSM ratio: 0.94), and voriconazole plasma concentrations were slightly raised (AUC(12)             (h)  LSM ratio: 1.14). All treatments and combinations were well tolerated, with no grade 3 or 4 adverse events observed during treatment. There was 1 adverse event-related trial withdrawal during treatment with fluconazole alone (leukocyturia). The most frequent adverse events were headache and blurred vision (11 and 8 volunteers, respectively), with blurred vision occurring exclusively during voriconazole-alone treatment. Pharmacokinetic interactions between etravirine and fluconazole or voriconazole are not expected to be clinically relevant; no dose adjustments are required during coadministration.
authors: Janssen Research & Development, LLC, Titusville, NJ, USA. tkakuda@its.jnj.com
authors: Thomas N
authors: TN
authors: Kakuda
authors: Rodica
authors: R
authors: Van Solingen-Ristea
authors: Fatima
authors: F
authors: Aharchi
authors: Goedele De
authors: GD
authors: Smedt
authors: James
authors: J
authors: Witek
authors: Steven
authors: S
authors: Nijs
authors: Veerle
authors: V
authors: Vyncke
authors: Richard M W
authors: RM
authors: Hoetelmans
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005838:Genotype; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065819:Voriconazole; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000935:Antifungal Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C451734:etravirine; D015725:Fluconazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole