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A Modeling and Simulation Approach to Characterize Methadone QT Prolongation Using Pooled Data From Five Clinical Trials in MMT Patients
Author(s) -
Florian J,
Garnett C E,
Nallani S C,
Rappaport B A,
Throckmorton D C
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.273
Subject(s) - medicine , qt interval , pharmacodynamics , clinical pharmacology , methadone , confidence interval , prolongation , pharmacokinetics , methadone maintenance , anesthesia , pharmacology
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. Clinical Pharmacology & Therapeutics (2012); 91 4, 666–672. doi: 10.1038/clpt.2011.273