Eriksson Ulf G, Mandema Jaap W, Karlsson Mats O, Frison Lars, Gisleskog Per Olsson, Wählby Ulrika, Hamrén Bengt, Gustafsson David, Eriksson Bengt I
AstraZeneca R&D Mölndal, Mölndal, Sweden.
Clin Pharmacokinet. 2003;42(7):687-701. doi: 10.2165/00003088-200342070-00006.
Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined.
Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model.
The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT.
The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
希美加群是一种口服直接凝血酶抑制剂，可迅速生物转化为其活性形式美拉加群。本群体分析的目的是，在接受皮下注射美拉加群和口服希美加群序贯给药以预防静脉血栓栓塞的骨科手术患者中，描述美拉加群的药代动力学及其对活化部分凝血活酶时间（APTT，一种体外凝血时间测量指标）的影响。为支持一项关键的剂量探索性研究的设计，研究了基于体重和计算的肌酐清除率的个体化给药的影响。
分析了在三项小剂量指导研究中获得的汇总数据。患者在手术开始前开始接受每日两次给药，单独皮下注射美拉加群或皮下注射美拉加群后口服希美加群的序贯方案，持续8 - 11天。使用非线性混合效应模型评估来自三项剂量指导试验中216例患者样本中美拉加群药代动力学的丰富数据（3326次观察）以及对APTT的药效学影响（2319次观察）。使用在关键剂量探索试验中入组的319例患者亚组中收集的稀疏数据对药代动力学和药效学模型进行验证。通过药代动力学 - 药效学模型模拟评估个体化给药对药代动力学和药效学变异性的影响。
皮下注射美拉加群和口服希美加群后，美拉加群的药代动力学可用具有一级吸收的单室模型很好地描述。美拉加群清除率与肾功能相关，以计算的肌酐清除率评估。群体清除率中位数（肌酐清除率70 mL/min），皮下制剂和口服制剂分别为5.3和22.9 L/h。口服希美加群后美拉加群相对于皮下注射美拉加群的生物利用度为23%。分布容积受体重影响。对于体重75kg的患者，皮下制剂和口服制剂的群体估计中位数分别为15.5和159L。APTT与美拉加群血浆浓度之间的关系可用幂函数很好地描述，在手术期间和术后早期斜率更陡，但不受任何协变量影响。模拟表明，基于肌酐清除率或体重的个体化给药对美拉加群药代动力学变异性或对APTT的影响没有临床相关影响。
个体化给药对美拉加群药代动力学和药效学变异性的影响相对较小，支持在包括轻度至中度肾功能损害患者在内的研究骨科手术患者群体中使用固定剂量方案。
