Ogawa Ryuichi, Kishi Ryoji, Mihara Kiyoshi, Takahashi Harumi, Takagi Akihiko, Matsumoto Naoki, Masuhara Keisou, Nakazawa Kiyoshi, Miyake Fumihiko, Kobayashi Shinichi, Echizen Hirotoshi
Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
J Clin Pharmacol. 2006 Jan;46(1):59-68. doi: 10.1177/0091270005283281.
Population pharmacokinetics (PK) of a sodium channel-blocking antiarrhythmic, pilsicainide, was studied using the nonlinear mixed-effects modeling technique in 91 patients with cardiac arrhythmias (80 suspected Brugada syndrome [BrS] and 11 with atrial fibrillation) who received an intravenous infusion of 10 mg of the drug. Population pharmacodynamic (PD) analysis was also performed using an effect compartment model. PD responses were assessed by changes in electrocardiogram (ECG) pattern (BrS-like elevation of ST-segment) and conduction parameters. The final PK model showed that gender (values were 50% lower in women than in men) and creatinine clearance were significant (P < .01) covariates of weight-normalized systemic clearance of pilsicainide. Patients who showed a BrS-like ECG pattern after the drug administration also showed a significantly (P < .01) greater prolongation in His-Purkinje conduction compared to the remaining patients. In conclusion, female gender, renal dysfunction, and the drug-induced BrS-like ECG morphology may be associated with augmented ECG responses to pilsicainide.
采用非线性混合效应建模技术，对91例心律失常患者（80例疑似Brugada综合征[BrS]和11例房颤患者）进行了钠通道阻滞剂抗心律失常药吡西卡尼的群体药代动力学（PK）研究，这些患者接受了10mg该药的静脉输注。还使用效应室模型进行了群体药效学（PD）分析。通过心电图（ECG）模式（类似BrS的ST段抬高）和传导参数的变化评估PD反应。最终的PK模型显示，性别（女性的值比男性低50%）和肌酐清除率是吡西卡尼体重标准化全身清除率的显著（P <.01）协变量。给药后出现类似BrS的ECG模式的患者与其余患者相比，His-Purkinje传导的延长也显著（P <.01）更大。总之，女性、肾功能不全以及药物诱导的类似BrS的ECG形态可能与吡西卡尼的ECG反应增强有关。
