Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis

作者：Marie Cullberg, Ulf G. Eriksson, Karin Wåhlander, Henry Eriksson, Sam Schulman, Magnus Olof Erik Karlsson · 发表于：Clinical Pharmacology & Therapeutics · 年份：2005 · DOI：10.1016/j.clpt.2004.11.001 · 被引用次数：29 · 研究领域：Venous Thromboembolism Diagnosis and Management、Atrial Fibrillation Management and Outcomes、Blood Coagulation and Thrombosis Mechanisms

OBJECTIVE: Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis. METHODS: A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models. RESULTS: The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respe...