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The pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran when administered with azithromycin and cefuroxime
Author(s) -
Dorani H.,
Schützer K.,
Sarich T.,
Wall U.,
Ohlsson L.,
Eriksson U.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.211
Subject(s) - ximelagatran , cefuroxime , pharmacokinetics , pharmacology , pharmacodynamics , cmax , direct thrombin inhibitor , azithromycin , medicine , antithrombin , antibiotics , tolerability , anticoagulant , antibacterial agent , anesthesia , chemistry , adverse effect , warfarin , heparin , atrial fibrillation , biochemistry , dabigatran
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. Clinical Pharmacology & Therapeutics (2005) 77 , P83–P83; doi: 10.1016/j.clpt.2004.12.211