, Volume 63, Issue 6, pp 571-581
Date: 27 Mar 2007

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

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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 Cmax. 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 Cmax, 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 Cmax of melagatran. Co-administration with the antibiotics did not change mean time to Cmax, 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.

Data described in this manuscript were presented in poster form at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) 2005 Congress, 2–6 March, Orlando, FL, USA.