Bayer HealthCare, Wuppertal, Germany.
Clin Pharmacokinet. 2011 Oct;50(10):675-86. doi: 10.2165/11595320-000000000-00000.
Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population.
A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described.
The pharmacokinetics of rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma rivaroxaban concentrations (≤500 μg/L).
Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.
利伐沙班是一种口服、直接的 Xa 因子抑制剂，目前处于预防和治疗血栓栓塞性疾病的临床开发后期。两项 II 期研究，ODIXa-DVT 和 EINSTEIN DVT，评估了口服利伐沙班（每日一次或每日两次）治疗急性深静脉血栓形成（DVT）的疗效和安全性。对这两项 II 期研究中患者的利伐沙班群体药代动力学和药效学进行了分析，以描述利伐沙班的药代动力学/药效学以及重要患者协变量与模型参数之间的关系。还进行了房颤（AF）患者的暴露模拟，以使用反映典型 AF 人群特征的修改后的人口统计学数据来预测利伐沙班的暴露。
使用来自这些患者的血浆样本建立了群体药代动力学模型。进行了各种模拟，以探索 DVT 患者中利伐沙班的药代动力学，并预测 AF 患者中的暴露情况。还描述了血浆利伐沙班浓度与凝血酶原时间、Xa 因子活性、HepTest®和活化部分凝血活酶时间之间的相关性。
DVT 患者的利伐沙班药代动力学在所有研究剂量下均一致且可预测。曲线下面积（AUC）随剂量呈依赖性增加。每日一次给予相同的总日剂量可实现更高的最大血浆浓度（Cmax）值（约 20%）和更低的谷浓度（最低）（C（trough））值（约 60%），而每日两次给予时则较低；然而，这些参数的 5 至 95 百分位范围重叠。利伐沙班清除率受年龄和肾功能的中度影响，分布容积受年龄、体重和性别影响；这些影响在观察到的个体间变异性内。在 AF 的虚拟患者人群中进行的模拟显示，在肌酐清除率为 30-49 mL/min 的患者中，每日一次给予 15mg 利伐沙班可达到 AUC 和 Cmax 值，与肾功能正常患者中每日一次给予 20mg 利伐沙班观察到的相似。凝血酶原时间与血浆利伐沙班浓度呈几乎线性相关（≤500μg/L）。
来自 II 期临床数据的群体分析表明，所有利伐沙班剂量的药代动力学和药效学均可预测，并受急性 DVT 患者预期人口统计学因素的影响。
