title: Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies.
abstract: OBJECTIVE
  Drug-drug interactions between etravirine and rifabutin or clarithromycin were examined in two separate open-label, randomized, two-period, crossover trials in HIV-negative, healthy volunteers.
  
  
  METHODS
  Rifabutin study: 16 participants received 300 mg of rifabutin once daily (14 days) and then 800 mg of etravirine twice daily (Phase 2 formulation; 21 days) plus 300 mg of rifabutin once daily (days 8-21). Clarithromycin study: 16 participants received 200 mg of etravirine twice daily (commercial formulation; 8 days) and then 500 mg of clarithromycin twice daily (13 days) plus 200 mg of etravirine twice daily (days 6-13). A 14 day washout period between treatments was mandatory in both studies. Full pharmacokinetic profiles of each drug and safety/tolerability were assessed.
  
  
  RESULTS
  Rifabutin decreased etravirine exposure by 37%; etravirine decreased rifabutin and 25-O-desacetyl rifabutin exposure by 17%. Clarithromycin increased etravirine exposure by 42%, whereas etravirine decreased clarithromycin exposure by 39% and increased 14-OH clarithromycin exposure by 21%. No serious adverse events were reported in either trial.
  
  
  CONCLUSIONS
  Short-term etravirine coadministration with rifabutin or clarithromycin was well tolerated. Etravirine can be coadministered with 300 mg of rifabutin once daily in the absence of an additional potent cytochrome P450 inducer. No dose adjustments are required upon etravirine/clarithromycin coadministration, but alternatives to clarithromycin are recommended when used for Mycobacterium avium complex prophylaxis or treatment.
authors.affiliation: Janssen Research & Development LLC, Titusville, NJ, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Kakuda
authors.forename: Brian
authors.initials: B
authors.lastname: Woodfall
authors.forename: Tine
authors.initials: T
authors.lastname: De Marez
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.forename: Kati
authors.initials: K
authors.lastname: Vandermeulen
authors.forename: Fatima
authors.initials: F
authors.lastname: Aharchi
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D017291:Clarithromycin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines; D017828:Rifabutin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D017828:Rifabutin; D017291:Clarithromycin
keywords: anti-infectives; non-nucleoside reverse transcriptase inhibitors; pharmacokinetics