Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Clin Pharmacol Ther. 2012 Apr;91(4):666-72. doi: 10.1038/clpt.2011.273. Epub 2012 Feb 29.
Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.
药代动力学（PK）-药效学建模和模拟用于建立美沙酮剂量、浓度与 Fridericia 心率校正 QT（QTcF）间期延长之间的联系，并确定与尖端扭转型室性心动过速（TdP）风险增加相关的剂量。浓度与 QTcF 之间的线性关系描述了美沙酮维持治疗（MMT）患者的五项临床试验数据。先前发表的群体 PK 模型充分描述了浓度-时间数据，并使用该模型进行了模拟。美沙酮浓度每增加 1,000ng/ml，平均（90%置信区间（CI））QTcF 延长 17（12，22）ms。基于该模型，剂量>120mg/天会使 QTcF 间期延长>20ms。该模型预测，在 160-200mg/天的剂量下，1-3%的患者会出现ΔQTcF >60ms，0.3-2.0%的患者会出现 QTcF >500ms。我们的预测与现有观察数据一致，并支持在接受美沙酮剂量>120mg/天的患者中进行心电图（ECG）监测和心律失常风险因素评估。
