Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran co-administered with different classes of antibiotics in healthy volunteers

Abstract

Objective: To study the effects of amoxicillin, doxycycline, ciprofloxacin, azithromycin, and cefuroxime on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, which is a substrate for the P-glycoprotein pump (P-gp) transporter but is not metabolized by the cytochrome P450 (CYP450) enzyme system.

Methods: Five parallel groups of 16 healthy volunteers received two sequential treatments. The first treatment was a single 36-mg dose of ximelagatran. During the second treatment period, one of the above antibiotics was given on days 1-5 after a washout of at least 2 days. A single 36-mg oral dose of ximelagatran was given on the mornings of days 1 and 5 of the second treatment period.

Results: No pharmacokinetic interactions were detected between ximelagatran and amoxicillin, doxycycline, or ciprofloxacin as the least-squares geometric mean treatment ratio of ximelagatran with-to-without antibiotic fell within the intervals of 0.80-1.25 for the area under the curve (AUC) and 0.7-1.43 for C(max). After co-administration with azithromycin, the least square mean ratio with-to-without antibiotic for AUC of melagatran was 1.60 (90% CI, 1.40-1.82) on day 1 and 1.41 (90% CI, 1.24-1.61) on day 5. For melagatran C(max), the corresponding ratios were 1.63 (90% CI, 1.38-1.92) and 1.40 (90% CI, 1.18-1.66). After co-administration with cefuroxime, the ratios were 1.23 (90% CI, 1.07-1.42) and 1.16 (90% CI, 0.972-1.38) for AUC and 1.33 (90% CI, 1.07-1.66) and 1.19 (90%CI, 0.888-1.58) for C(max) of melagatran. Co-administration with the antibiotics did not change mean time to C(max), half-life, or renal clearance of melagatran. The melagatran plasma concentration-response relationship for activated partial thromboplastin time (APTT) prolongation was not altered by any of the studied antibiotics, but the increased plasma concentrations of melagatran after co-administration of ximelagatran with azithromycin resulted in a minor increase in the mean maximum APTT of about 15%.

Conclusion: The pharmacokinetics of ximelagatran were not affected by amoxicillin, doxycycline, or ciprofloxacin. Melagatran exposure was increased when ximelagatran was co-administered with azithromycin and, to a lesser extent, with cefuroxime. APTT was not significantly altered by any of the antibiotics.