ABSTRACT:A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp-overexpressing Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.i.d. on days 2 to 5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6, the least-squares mean estimates (90% confidence intervals) for the ratio of ximelagatran with erythromycin to ximelagatran given alone were 1.82 (1.64-2.01) for the area under the concentration-time curve and 1.74 (1.52-2.00) for the maximum plasma concentration of melagatran, the active form of ximelagatran. Neither the slope nor the intercept of the melagatran plasma concentration-effect relationship for activated partial thromboplastin time statistically significantly differed as a function of whether or not erythromycin was administered with ximelagatran. Ximelagatran was well tolerated regardless of whether it was administered with erythromycin. Erythromycin inhibited P-gp-mediated transport of both ximelagatran and melagatran in vitro and decreased the biliary excretion of melagatran in the rat. These results indicate that the mechanism of the pharmacokinetic interaction between oral ximelagatran and erythromycin may involve inhibition of transport proteins, possibly P-gp, resulting in decreased melagatran biliary excretion and increased bioavailability of melagatran.Ximelagatran is an oral direct thrombin inhibitor (oral DTI) which is available for the prevention of venous thromboembolic events in patients undergoing elective hip or knee replacement surgery and is being developed for the treatment of venous thromboembolic events, stroke prevention in patients with atrial fibrillation, and the secondary prevention of cardiovascular events after myocardial infarction (Bergsrud and Gandhi,

In this randomized, 2-way crossover study, the potential for interaction was investigated between atorvastatin and ximelagatran, an oral direct thrombin inhibitor. Healthy female and male volunteers (n = 16) received atorvastatin 40 mg as a single oral dose and, in a separate study period, ximelagatran 36 mg twice daily for 5 days plus a 40-mg oral dose of atorvastatin on the morning of day 4. In the 15 subjects completing the study, no pharmacokinetic interaction was detected between atorvastatin and ximelagatran for all parameters investigated, including melagatran (the active form of ximelagatran) area under the plasma concentration versus time curve (AUC) and maximum plasma concentration, atorvastatin acid AUC, and AUC of active 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors. Atorvastatin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between atorvastatin and ximelagatran was observed in this study.

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:

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.

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