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Keywords:

  • cytochrome P450;
  • drug–drug interactions;
  • healthy subjects;
  • pharmacokinetics;
  • rifampicin;
  • transporters

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Darexaban is an oral direct factor Xa inhibitor developed as an antithrombotic for several indications. Several other new oral anticoagulants are metabolized via CYP3A4 and transported by P-glycoprotein, displaying clinically relevant drug interactions with rifampicin and ketoconazole.

• Darexaban is almost entirely metabolized to darexaban glucuronide, which is the main active moiety. In vitro, CYP3A4 metabolism is not involved in the formation or metabolism of darexaban glucuronide; and darexaban, but not darexaban glucuronide, is a P-glycoprotein substrate in vitro.

WHAT THIS STUDY ADDS

• The study shows that rifampicin does not affect the pharmacokinetic profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug−drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.

• This study was carried out to confirm the susceptibility of darexaban/darexaban glucuronide to CYP3A4 and P-glycoprotein induction in vivo in humans.

AIMS We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect.

METHODS In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4−14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1−14. The maximal plasma drug concentration (Cmax) and exposure [area under the plasma concentration–time curve from time zero to time of quantifiable measurable concentration; (AUClast) or AUClast extrapolated to infinity (AUC)] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and Cmax ratios were predefined as 80−125%.

RESULTS Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUClast with/without rifampicin was 1.08 (1.00, 1.16). The Cmax of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated.

CONCLUSIONS Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug−drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.