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 (C(max)) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUC(last)) or AUC(last) extrapolated to infinity (AUC(∞))] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C(max) ratios were predefined as 80-125%. RESULTS: Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC(last) with/without rifampicin was 1.08 (1.00, 1.16). The C(max) 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.
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 (C(max)) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUC(last)) or AUC(last) extrapolated to infinity (AUC(∞))] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C(max) ratios were predefined as 80-125%. RESULTS:Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC(last) with/without rifampicin was 1.08 (1.00, 1.16). The C(max) 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.
Authors: Harvey D White; Michael Gruber; Jan Feyzi; Scott Kaatz; Hung-Fat Tse; Steen Husted; Gregory W Albers Journal: Arch Intern Med Date: 2007-02-12
Authors: Matthew R Reynolds; Jignesh Shah; Vidal Essebag; Brian Olshansky; Paul A Friedman; Tomy Hadjis; Robert Lemery; Tristram D Bahnson; David S Cannom; Mark E Josephson; Peter Zimetbaum Journal: Am J Cardiol Date: 2006-01-04 Impact factor: 2.778