We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin.
- Authors
Härtter, Sebastian; Koenen-Bergmann, Michael; Sharma, Ashish; Nehmiz, Gerhard; Lemke, Ute; Timmer, Wolfgang; Reilly, Paul A.
- Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Dabigatran etexilate is an oral prodrug that is rapidly converted to dabigatran, a direct and reversible thrombin inhibitor. • Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system, and dabigatran does not affect the metabolism of other drugs that utilize this system, leading to a low potential for drug-drug interactions. • Dabigatran etexilate, but not dabigatran, is a P-glycoprotein (P-gp) substrate, and the bioavailability of dabigatran may be altered by P-gp inhibitors or inducers. WHAT THIS STUDY ADDS • Administration of rifampicin (a strong P-gp inducer) for 7 days before a single dose of dabigatran etexilate resulted in a significant reduction in the bioavailability of dabigatran compared with administration of dabigatran etexilate alone. • Within 7 days following the cessation of rifampicin administration, the bioavailability of dabigatran returned almost to baseline values. • Rifampicin is not recommended for use with dabigatran etexilate because of the potential for reduced systemic exposure to dabigatran. AIMS 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 (AUC0-∞) and maximal plasma concentration ( Cmax) 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 AUC0-∞ and 34.5% (90% confidence interval 26.9, 44.1%) for Cmax, 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 AUC0-∞ and Cmax 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.
- Subjects
BIOAVAILABILITY; RIFAMPIN; PRODRUGS; ORAL medicine; ANTITHROMBINS; CYTOCHROME P-450; P-glycoprotein
- Publication
British Journal of Clinical Pharmacology, 2012, Vol 74, Issue 3, p490
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/j.1365-2125.2012.04218.x