¹AstraZeneca R&D Mölndal, AstraZeneca LP, Mölndal, Sweden

Abstract

Background: Ximelagatran is bioconverted to its active form melagatran. It has a low potential for drug interactions as its metabolism is independent of CYP450 enzymes.

Methods: Healthy volunteers (n=32) received ximelagatran 36 mg as a single oral dose and, after a 2-day washout period, either azithromycin 500 mg on Day 1 and 250 mg qd on Days 2 to 5, or cefuroxime 250 mg bid on Days 1 to 4 and 250 mg on Day 5, with a 36 mg dose of ximelagatran on Days 1 and 5.

Results: The least squares mean estimates for melagatran exposure (AUC) ratios with:without antibiotic were 1.60 (90% CI, 1.40–1.82) and 1.41 (90% CI, 1.24–1.61) on Days 1 and 5 of the azithromycin period. For cefuroxime, the corresponding ratios were 1.23 (90% CI, 1.07–1.42) and 1.16 (90% CI, 0.972–1.38). The mean time to C_max, elimination half-life, and renal clearance of melagatran were not affected by administering ximelagatran with either antibiotic. Plasma antibiotic concentrations were not affected by coadministration of ximelagatran. Neither antibiotic affected melagatran-dependent prolongation of activated partial thromboplastin time. Ximelagatran given with the antibiotics was well tolerated.

Conclusion: Melagatran exposure was increased by coadministration with azithromycin and to a lesser extent with cefuroxime, but the pharmacodynamics and tolerability of ximelagatran and the plasma concentrations of the antibiotics were unaffected.