Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M
Clinical Pharmacology, Pharmacometry, Bayer HealthCare AG, Wuppertal, Germany.
Int J Clin Pharmacol Ther. 2007 Jun;45(6):335-44. doi: 10.5414/cpp45335.
Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor being developed for the prevention and treatment of thromboembolic disorders. This analysis aimed to define population models for the pharmacokinetics (PK) and pharmacodynamics (PD) ofrivaroxaban in healthy males.
Non-linear, mixed-effect modeling was used to analyze rivaroxaban plasma concentration and PD data (FXa activity and clotting tests) from subjects in a phase I, multiple-ascending-dose study. Subjects received 5 mg rivaroxaban once, twice or three times daily, or 10, 20 or 30 mg rivaroxaban twice daily.
The population PK of rivaroxaban were well described by an oral, two-compartment model with first-order absorption and elimination from the central compartment. Population mean estimates for apparent oral clearance and volume of distribution for the central compartment were 9.2 1/h and 55 1, respectively, with moderate inter-individual variability (17.4% and 30.7%, respectively). Total volume of distribution for rivaroxaban at steady state was approximately 70 1. Residual (unexplained) variability was 25%. FXa activity correlated with rivaroxaban plasma concentrations following an inhibitory Emax model; prothrombin time (PT) and rivaroxaban plasma concentrations correlated with a linear model, with a slope of 4.6 s/(100 microg/1). Inter-individual variability was low for the correlation with PT. The models derived were used to define sampling windows for population PK/PD modeling in Phase II studies.
This analysis confirms that rivaroxaban has predictable, dose-proportional PK and PD. The linear correlation between rivaroxaban plasma concentrations and PT suggests that this test might be useful to assess rivaroxaban exposure in patients, if required.
利伐沙班（BAY 59 - 7939）是一种口服的直接Xa因子（FXa）抑制剂，正被开发用于预防和治疗血栓栓塞性疾病。本分析旨在确定健康男性中利伐沙班的药代动力学（PK）和药效动力学（PD）的群体模型。
采用非线性混合效应模型分析来自一项I期多剂量递增研究受试者的利伐沙班血浆浓度和PD数据（FXa活性和凝血试验）。受试者每日接受一次、两次或三次5mg利伐沙班，或每日两次接受10、20或30mg利伐沙班。
利伐沙班的群体PK通过具有一级吸收和从中央室消除的口服二室模型得到很好的描述。中央室表观口服清除率和分布容积的群体均值估计分别为9.2 l/h和55 l，个体间变异性中等（分别为17.4%和30.7%）。利伐沙班稳态时的总体分布容积约为70 l。残差（无法解释的）变异性为25%。FXa活性与利伐沙班血浆浓度符合抑制性Emax模型；凝血酶原时间（PT）与利伐沙班血浆浓度符合线性模型，斜率为4.6 s/(100 μg/l)。与PT的相关性个体间变异性较低。所推导的模型用于确定II期研究中群体PK/PD建模的采样窗口。
本分析证实利伐沙班具有可预测的、剂量成比例的PK和PD。利伐沙班血浆浓度与PT之间的线性相关性表明，如果需要，该检测可能有助于评估患者中利伐沙班的暴露情况。
