Low Potential for Interactions Between Melagatran/Ximelagatran and Other Drugs, Food, or Alcohol

ABSTRACT

Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration (C _max) of up to ∼80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.

Ximelagatran - pharmacokinetics - pharmacodynamics - food:drug interactions - cytochrome P450

REFERENCES

• 1 Malhotra O P, Nesheim M E, Mann K G. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins.  J Biol Chem. 1985;  260 279-287
• 2 Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets.  Thromb Haemost. 1999;  81 396-399
• 3 Franco V, Polanczyk C A, Clausell N, Rohde L E. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols.  Am J Med. 2004;  116 651-656
• 4 Kaminsky L S, Zhang Z Y. Human P450 metabolism of warfarin.  Pharmacol Ther. 1997;  73 67-74
• 5 Wells P S, Holbrook A M, Crowther N R, Hirsh J. Interactions of warfarin with drugs and food.  Ann Intern Med. 1994;  121 676-683
• 6 Schaefer M G, Plowman B K, Morreale A P, Egan M. Interaction of rofecoxib and celecoxib with warfarin.  Am J Health Syst Pharm. 2003;  60 1319-1323
• 7 Andrus M R. Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature.  Pharmacotherapy. 2004;  24 285-290
• 8 Sax M J. Clinically important adverse effects and drug interactions with H2-receptor antagonists: an update.  Pharmacotherapy. 1987;  7 110S-115S
• 9 Izzo A A, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review.  Drugs. 2001;  61 2163-2175
• 10 Yuan C S, Wei G, Dey L et al.. Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled trial.  Ann Intern Med. 2004;  141 23-27
• 11 Zhou S, Chan E, Pan S Q, Huang M, Lee E J. Pharmacokinetic interactions of drugs with St John's wort.  J Psychopharmacol. 2004;  18 262-276
• 12 Hirsh J, Fuster V, Ansell J, Halperin J L. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.  J Am Coll Cardiol. 2003;  41 1633-1652
• 13 Wittkowsky A K, Boccuzzi S J, Wogen J, Wygant G, Patel P, Hauch O. Frequency of concurrent use of warfarin with potentially interacting drugs.  Pharmacotherapy. 2004;  24 1668-1674
• 14 Eriksson U G, Bredberg U, Hoffmann K J et al.. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans.  Drug Metab Dispos. 2003;  31 294-305
• 15 Johansson L C, Frison L, Logren U, Fager G, Gustafsson D, Eriksson U G. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 381-392
• 16 Wolzt M, Wollbratt M, Svensson M, Wåhlander K, Grind M, Eriksson U G. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.  Eur J Clin Pharmacol. 2003;  59 537-543
• 17 Clement B, Lopian K. Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug.  Drug Metab Dispos. 2003;  31 645-651
• 18 Bredberg E, Andersson T B, Frison L et al.. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions.  Clin Pharmacokinet. 2003;  42 765-777
• 19 Sarich T C, Schützer K M, Dorani H et al.. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran.  J Clin Pharmacol. 2004;  44 928-934
• 20 Rodin S M, Johnson B F. Pharmacokinetic interactions with digoxin.  Clin Pharmacokinet. 1988;  15 227-244
• 21 Koren G, Woodland C, Ito S. Toxic digoxin-drug interactions: the major role of renal P-glycoprotein.  Vet Hum Toxicol. 1998;  40 45-46
• 22 Sarich T C, Schützer K M, Wollbratt M, Wall U, Kessler E, Eriksson U G. No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers.  J Clin Pharmacol. 2004;  44 935-941
• 23 Tomlinson B, Young R P, Chan T Y, Critchley J A, Chan J C. Monitoring may need to be prolonged in patients given warfarin and amiodarone.  BMJ. 1996;  313 301-302
• 24 Sanoski C A, Bauman J L. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy.  Chest. 2002;  121 19-23
• 25 Teng R, Sarich T C, Eriksson U G et al.. A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor.  J Clin Pharmacol. 2004;  44 1063-1071
• 26 Roden D M. Mechanisms underlying variability in response to drug therapy: implications for amiodarone use.  Am J Cardiol. 1999;  84 29R-36R
• 27 Francis C W, Berkowitz S D, Comp P C et al.. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.  N Engl J Med. 2003;  349 1703-1712
• 28 Eriksson U, Baathe S, Hamrén B, Wollbratt M, Wolzt M, Grind M. Predictable pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor, in nonvalvular atrial fibrillation patients receiving long-term treatment.  Pathophysiol Haemost Thromb. 2002;  32(Suppl 2) 56 , Abstract
• 29 Dorani H, Schützer K, Sarich T, Wall U, Ohlsson L, Eriksson U G. The pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran when administered with erythromycin.  Pathophysiol Haemost Thromb. 2004;  33(Suppl 2) 99 , Abstract
• 30 Dorani H, Schützer K M, Sarich T C, Wall U, Ohlsson L, Eriksson U G. The pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran when administered with azithromycin and cefuroxime.  Clin Pharmacol Ther. 2005;  77 83 , Abstract
• 31 Dorani H, Schützer K M, Sarich T C, Wall U, Ohlsson L, Eriksson U G. No effect of amoxicillin, doxycycline, and ciprofloxacin on the pharmacokinetics and pharmacodynamics of ximelagatran.  Clin Pharmacol Ther. 2005;  77 46 , Abstract
• 32 Eriksson U G, Bredberg U, Gislén K et al.. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects.  Eur J Clin Pharmacol. 2003;  59 35-43
• 33 Wernevik L C, Nyström P, Johnsson G, Nakanishi T, Eriksson U G. Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran in young healthy Japanese men.  Clin Pharmacokinet. 2005;  , In press
• 34 Sarich T C, Johansson S, Schützer K J et al.. The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct inhibitor, are unaffected by a single dose of alcohol.  J Clin Pharmacol. 2004;  44 388-393
• 35 Fager G, Cullberg M, Eriksson-Lepkowska M, Frison L, Eriksson U G. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid.  Eur J Clin Pharmacol. 2003;  59 283-289