title: Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug.
abstract: OBJECTIVE
  Bedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5-6 months), complicating evaluations of drug-drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach.
  
  
  METHODS
  Pharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments.
  
  
  RESULTS
  Rifamycin co-administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks.
  
  
  CONCLUSIONS
  Rifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24 Uppsala, Sweden elin.svensson@farmbio.uu.se.
authors.forename: Elin M
authors.initials: EM
authors.lastname: Svensson
authors.affiliation: Department of Clinical Research, Global Alliance for TB Drug Development, New York, NY, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Murray
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, PO Box 591, 751 24 Uppsala, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D064687:Diarylquinolines / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline; D012293:Rifampin; C018421:rifapentine
keywords: drug-drug interactions; population pharmacokinetics; tuberculosis