title: Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin.
abstract: OBJECTIVE
  This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.
  
  
  METHODS
  This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2-8, and single doses of dabigatran etexilate on days 9, 16 and 23.
  
  
  RESULTS
  Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration-time curve (AUC(0-∞)) and maximal plasma concentration (C(max)) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC(0-∞) and 34.5% (90% confidence interval 26.9, 44.1%) for C(max), indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC(0-∞) and C(max) of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.
  
  
  CONCLUSIONS
  Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany. sebastian.haertter@boehringer-ingelheim.com
authors.forename: Sebastian
authors.initials: S
authors.lastname: Härtter
authors.forename: Michael
authors.initials: M
authors.lastname: Koenen-Bergmann
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.forename: Gerhard
authors.initials: G
authors.lastname: Nehmiz
authors.forename: Ute
authors.initials: U
authors.lastname: Lemke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Timmer
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D001682:Biological Availability; D000069604:Dabigatran; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D011355:Prodrugs; D011725:Pyridines / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D020719:Glucuronides; D011355:Prodrugs; D011725:Pyridines; D000069604:Dabigatran; D012293:Rifampin