Effect of erythromycin on the pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran and its active form melagatran

Abstract

Background Ximelagatran (Exanta™, AstraZeneca), an oral direct thrombin inhibitor for the prevention and treatment of thromboembolic disorders, is rapidly absorbed and bioconverted to its active form melagatran. The metabolism of ximelagatran is independent of CYP450 enzymes and hence it has a low potential for drug interactions. This study evaluated the effect of erythromycin on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran. Methods: An open, sequential, single-centre study in healthy volunteers (n=16; mean age 24 years, range 20–32 years) with ximelagatran 36mg on Day 1, then erythromycin 500mg TID on Days 2–5 followed by ximelagatran 36 mg plus erythromycin on Day 6. Results: For melagatran, AUC and Cmax geometric mean ratios for combined therapy (Day 6) relative to monotherapy (Day 1) were 1.82 (90% CI, 1.64–2.01) and 1.74 (90% CI, 1.52–2.00), respectively, (n=15), falling outside of the predefined bounds for no interaction. Geometric mean ratios for tmax and t1/2 of melagatran were 1.14 and 0.93, respectively. The erythromycin-associated elevation in plasma melagatran concentrations increased the peak activated partial thromboplastin time (aPTT) prolongation from 41s to 44s. Ximelagatran was well tolerated alone, and in combination with erythromycin. Conclusions: This study showed evidence of a pharmacokinetic interaction between ximelagatran and erythromycin with respect to melagatran PK, which is being investigated, but only a small effect on aPTT. Clinical Pharmacology & Therapeutics (2004) 75, P78–P78; doi: 10.1016/j.clpt.2003.11.295