Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
J Thromb Haemost. 2011 Nov;9(11):2168-75. doi: 10.1111/j.1538-7836.2011.04498.x.
Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity.
To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters.
A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling.
The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily.
The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.
达比加群酯（DE）是达比加群的口服前体药物，达比加群是一种凝血酶抑制剂，具有强大的抗凝和抗血栓活性。
从随机评估长期抗凝治疗（RE-LY）试验中描述非瓣膜性心房颤动（AF）患者达比加群的药代动力学特征，并定量分析选定因素对药代动力学（PK）模型参数的影响。
共分析了接受 DE 110 或 150 mg 每日两次治疗的 9522 例患者的 27706 个达比加群血浆浓度，采用非线性混合效应模型进行分析。
达比加群的药代动力学最好用具有一级吸收的两室分布模型来描述。肌酐清除率（CRCL）、年龄、性别、心力衰竭和“南亚”亚组等协变量对达比加群的表观清除率表现出统计学上显著的影响。体重和血红蛋白显著影响中央室的表观分布容积。质子泵抑制剂、胺碘酮和维拉帕米的伴随用药显著影响生物利用度。然而，除肾功能状态外，所有确定的统计学上显著的因素仅显示出较小至中等程度的影响（稳态时暴露量变化<26%）。基于最终人群 PK 模型的模拟，对于 CRCL 为 15-30 mL min(-1)的严重肾功能受损患者和接受 150 mg 每日两次治疗的肾功能正常患者，每日两次给予 75 mg 的剂量将产生相似的暴露。
该分析提供了来自 RE-LY 的 AF 患者人群中达比加群的全面 PK 特征。除肾功能外，研究的所有协变量均不需要调整剂量。
