BACKGROUND: Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. OBJECTIVE: To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events. METHODS: A population pharmacokinetic model was developed based on data from three phase II studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model. RESULTS: Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure. CONCLUSION: The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.
BACKGROUND:Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. OBJECTIVE: To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events. METHODS: A population pharmacokinetic model was developed based on data from three phase II studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model. RESULTS:Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure. CONCLUSION: The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.
Authors: Marita Larsson; Martin Ahnoff; Anna Abrahamsson; Ulrika Logren; Christina Fakt; Irene Ohrman; Bengt Arne Persson Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2003-01-15 Impact factor: 3.205
Authors: D Gustafsson; T Antonsson; R Bylund; U Eriksson; E Gyzander; I Nilsson; M Elg; C Mattsson; J Deinum; S Pehrsson; O Karlsson; A Nilsson; H Sörensen Journal: Thromb Haemost Date: 1998-01 Impact factor: 5.249
Authors: Gregory W Albers; Hans-Christoph Diener; Lars Frison; Margaretha Grind; Mark Nevinson; Stephen Partridge; Jonathan L Halperin; Jay Horrow; S Bertil Olsson; Palle Petersen; Alec Vahanian Journal: JAMA Date: 2005-02-09 Impact factor: 56.272
Authors: Eva Bredberg; Tommy B Andersson; Lars Frison; Annelie Thuresson; Susanne Johansson; Maria Eriksson-Lepkowska; Marita Larsson; Ulf G Eriksson Journal: Clin Pharmacokinet Date: 2003 Impact factor: 6.447
Authors: Bengt I Eriksson; Giancarlo Agnelli; Alexander T Cohen; Ola E Dahl; Patrick Mouret; Nadia Rosencher; Christina Eskilson; Ingela Nylander; Lars Frison; Mats Ogren Journal: Thromb Haemost Date: 2003-02 Impact factor: 5.249
Authors: Michael Wolzt; Maria Wollbratt; Mia Svensson; Karin Wåhlander; Margaretha Grind; Ulf G Eriksson Journal: Eur J Clin Pharmacol Date: 2003-09-04 Impact factor: 2.953