Abstract
Background: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development as an anticoagulant for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran.
Objective: To investigate the effect of severe renal impairment on the pharmacokinetics and pharmacodynamics of melagatran following administration of subcutaneous melagatran and oral ximelagatran.
Study design: This was a nonblinded randomised crossover study with 2 study days, separated by a washout period of 1–3 weeks. Twelve volunteers with severe renal impairment and 12 controls with normal renal function were included, with median (range) glomerular filtration rates (GFR) of 13 (5–24) and 86 (70–105) mL/min, respectively. All volunteers received, in a randomised sequence, a 3mg subcutaneous injection of melagatran and a 24mg immediate-release tablet of ximelagatran. Blood samples were collected up to 12 and 14 hours after administration of the subcutaneous and oral doses, respectively, for determination of melagatran plasma concentrations and the activated partial thromboplastin time (APTT), an ex vivo measurement of coagulation time. Urine was collected for 24 hours after each dose for determination of melagatran concentration.
Results: For the volunteers with severe renal impairment, the area under the plasma concentration-time curve (AUC) and the half-life of melagatran were significantly higher than in the control group with normal renal function. Least-squares mean estimates of the ratios of the mean AUC for volunteers with severe renal impairment and controls (95% confidence intervals) were 4.03 (3.29–4.93) after subcutaneous melagatran and 5.33 (3.76–7.56) after oral ximelagatran. This result was related to the decreased renal clearance (CLr) of melagatran, which was linearly correlated with GFR. In the severe renal impairment and control groups, respectively, the mean CLr of melagatran was 12.5 and 81.3 mL/ min after subcutaneous administration of melagatran and 14.3 and 107 mL/min after oral administration of ximelagatran. There was a nonlinear relationship between the APTT ratio (postdose/predose APTT value) and melagatran plasma concentration. A statistically significant higher slope of the concentration-effect relationship, described by linear regression of the APTT ratio versus the square root of melagatran plasma concentrations, was estimated for the group with severe renal impairment compared to the control group; however, the increase in slope was minor and the estimated differences in APTT ratio between the groups in the studied concentration range was less than 10% and not considered clincially relevant. Ximelagatran and melagatran were well tolerated in both groups.
Conclusions: After administration of subcutaneous melagatran and oral ximelagatran, subjects with severe renal impairment had significantly higher melagatran exposure and longer half-life because of lower CLr of melagatran compared with the control group with normal renal function, suggesting that a decrease in dose and/or an increase in the administration interval in patients with severe renal impairment would be appropriate.
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References
Weitz JI, Hirsh J. New anticoagulant drags. Chest 2001; 119 (1 Suppl.): 95S–107S
Eriksson BI, Arfwidsson A-C, Frison L, et al. A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002; 87: 231–7
Eriksson BI, Bergqvist D, Kälebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441–7
Eriksson BI, Agnelli G, Cohen AT, et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement. The METHRO III study. Thromb Haemost 2003; 89: 288–96
Heit JA, Colwell CW, Francis CW, et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001; 161: 2215–21
Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind trial. Ann Intern Med 2002; 137: 648–55
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: 358–63
Eriksson H, Wåhlander K, Gustafsson D, et al. A randomized, 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. Thromb Haemost 2003; 1: 41–7
Wåhlander K, Lapidus L, Olsson CG, et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res 2002; 107: 93–9
Petersen P, Grind M, Adler A, SPORTIF II Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: SPORTIF II. a dose-guiding, tolerability and safety study. J Am Coll Cardiol. 2003; 41: 1445–51
Gustafsson D, Nyström J-E, 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: 171–81
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: 294–305
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. 2003; 59: 35–43
Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003 2003; 42(4): 381–92
Eriksson UG, Mandema JW, Karlsson MO, et al. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis. Clin Pharmacokinet 2003; 42: 687–701
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41
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: 47–55
Brater DC. Measurement of renal function during drag development. Br J Clin Pharmacol 2002; 54: 87–95
Acknowledgements
The authors thank Ulrika Logren and colleagues at DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, for performing the determination of melagatran concentrations in biological samples. The study was sponsored by AstraZeneca.
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Eriksson, U.G., Johansson, S., Attman, PO. et al. Influence of Severe Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Ximelagatran and Subcutaneous Melagatran. Clin Pharmacokinet 42, 743–753 (2003). https://doi.org/10.2165/00003088-200342080-00003
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DOI: https://doi.org/10.2165/00003088-200342080-00003