Decrease in the oral bioavailability of dabigatran etexilate after co‐medication with rifampicin

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. AIMSThis study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate. METHODSThis 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. RESULTSTwenty-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. CONCLUSIONSAdministration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.

Pharmacogenetics in Oral Antithrombotic Therapy

“…The prodrug dabigatran etexilate is a substrate for the p-glycoprotein drug efflux transporter encoded by the ABCB1 gene. [23][24][25] The same GWAS from the subset of RE-LY patients found that the ABCB1 rs4148738 polymorphism is associated with an increase in peak plasma concentrations of dabigatran. 22 However, there was no association between dabigatran concentration and adverse events (ie, bleeding, ischemic events), making the clinical consequences of ABCB1 polymorphisms on dabigatran bioavailability uncertain.…”

Target-specific oral anticoagulants and the hospitalist

“…The use of TSOACs with other anticoagulants, platelet inhibitors, and nonsteroidal anti-inflammatory drugs increases bleeding risk. All TSOACs interact with the P-gp transporter and interact to varying extents with CYP isoenzyme 3A4 (CYP3A4) [25,[63][64][65][66][67][68]. The greatest CYP3A4 interactions are with apixaban (~25%) [64], followed by rivaroxaban (18%) [69].…”

Drug Interactions of New Oral Anticoagulants: Inside and Outside Table Cells

“…Показатели снижения плазменных кон-центраций НОАК под влиянием рифампицина получены в исследованиях с участием здоровых добровольцев при его назначении в дозе 600 мг/сут [23][24][25][26]. В ев-ропейской таблице эти показатели приведены дважды.…”