Objective: To investigate the influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran.
Study design: This was an open-label, randomised, 3 × 3 crossover study with 4 study days, separated by washout periods of 7 days.
Subjects: Subjects comprised 6 healthy young men (aged 20–27 years) and 12 healthy older men and women (aged 56–70 years).
Methods: All subjects received a 2mg intravenous infusion of melagatran over 10 minutes followed, in randomised sequence, by a 20mg immediate-release tablet of ximelagatran with breakfast, a 20mg immediate-release tablet of ximelagatran while fasting, and a 7.5mg subcutaneous injection of ximelagatran. The primary variables were the plasma concentration of melagatran, the active form of ximelagatran, and the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin.
Results: After oral and subcutaneous administration, ximelagatran was rapidly absorbed and biotransformed to melagatran, its active form and the dominant compound in plasma. The metabolite pattern in plasma and urine was similar in young and older subjects after both oral and subcutaneous administration of ximelagatran. Clearance of melagatran was correlated with renal function, resulting in about 40% (after intravenous melagatran) to 60% (after oral and subcutaneous ximelagatran) higher melagatran exposure in the older than in the young subjects. Renal clearance of melagatran, determined after intravenous administration of melagatran, was 7.7 L/h and 4.9 L/h in the young and older subjects, respectively. The interindividual variability in the area under the melagatran plasma concentration-time curve was low following all regimens (coefficient of variation 12–25%). The mean bioavailability of melagatran in young and older subjects was approximately 18 and 21%, respectively, following oral administration of ximelagatran, and 38 and 45%, respectively, following subcutaneous administration of ximelagatran. The bioavailability of melagatran following oral administration of ximelagatran was unaffected by whether subjects were fed or fasting, although the plasma concentration of melagatran peaked about 1 hour later under fed than fasting conditions, due to delayed gastric emptying of the immediate-release tablet formulation used. The APTT was prolonged with increasing melagatran plasma concentrations and the concentration-effect relationship was independent of age.
Conclusion: There were no age-dependent differences in the absorption and biotransformation of ximelagatran, and the observed differences in exposure to melagatran can be explained by differences in renal function between the young and older subjects.
Tegos TJ, Kalodiki E, Daskalopoulou SS, et al. Stroke: epidemiology, clinical picture, and risk factors: part I of III. Angiology 2000; 51: 793–808PubMedCrossRefGoogle Scholar
Williams GR, Jiang JG, Matchar DB, et al. Incidence and occurrence of total (first-ever and recurrent) stroke. Stroke 1999; 30: 2523–8PubMedCrossRefGoogle Scholar
Nordström M, Lindblad B, Bergqvist D, et al. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155–60PubMedCrossRefGoogle Scholar
Anderson Jr FA, Wheeler HB, Goldberg RJ, et al. A populationbased perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–8PubMedCrossRefGoogle Scholar
Elg M, Gustafsson D, Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 1997; 78: 1286–92PubMedGoogle Scholar
Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94: 187–97PubMedCrossRefGoogle Scholar
Gustafsson D, Antonsson T, Bylund R, et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110–8PubMedGoogle Scholar
Mehta JL, Chen L, Nichols WW, et al. Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 1998; 31: 345–51PubMedCrossRefGoogle Scholar
Eriksson BI, Carlsson S, Halvarsson M, et al. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular-weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 1997; 78: 1404–7PubMedGoogle Scholar
Mattsson C, Björkman JA, Ulvinge JC. Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in a canine model of coronary artery thrombolysis. Fibrinolysis Proteolysis 1997; 11: 121–8CrossRefGoogle Scholar
Eriksson BI, Bergqvist D, Kälebo P, et al. The oral, direct thrombin inhibitor, ximelagatran, and its active form, melagatran, in ascending doses compared with dalteparin for prevention of venous thromboembolism after total hip or total knee replacement: The METHRO II study. Lancet 2002; 360: 1441–7PubMedCrossRefGoogle Scholar
Eriksson H, Eriksson UG, Frison L, et al. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 1999; 81: 358–63PubMedGoogle Scholar
Eriksson H, Wåhlander K, Gustafsson D, et al. A randomised, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003; 1: 41–7PubMedCrossRefGoogle Scholar
Petersen P, SPORTIF II Investigators. Long-term treatment of patients using the new oral direct thrombin inhibitor ximelagatran (pINN, formerly H 376/95) versus warfarin in moderate to high stroke risk patients with atrial fibrillation. J Neurol Sci 2001; 187 Suppl. 1: S124–5Google Scholar
Eriksson UG, 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: 294–305PubMedCrossRefGoogle Scholar
Gustafssson D, Nystrom J, Carlsson S, et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171–81CrossRefGoogle Scholar
Eriksson UG, 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. In pressGoogle Scholar
Hämmerlein A, Derendorf H, Lowenthal D. Pharmacokinetics and pharmacodynamics changes in the elderly: clinical implications. Clin Pharmacokinet 1998; 35: 49–64PubMedCrossRefGoogle Scholar
Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999; 45: 243–53PubMedCrossRefGoogle Scholar
Rainfray M, Richard-Harston S, Salles-Montaudon N, et al. Effects of aging on kidney function and implications for medical practice. Presse Med 2000; 29: 1373–8PubMedGoogle Scholar
Marchant B. Pharmacokinetic factors influencing variability in human drug response. Scand J Rheumatol Suppl 1981; 39: 5–14PubMedCrossRefGoogle Scholar
Larsson M, Logren U, Ahnoff M, et al. Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography: mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 766: 47–55PubMedCrossRefGoogle Scholar
Mattsson C, Menschiek-Lundin A, Wåhlander K, et al. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thromb Haemost 2001; 86: 611–5PubMedGoogle Scholar