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- Title
A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients.
- Authors
Florian, J; Garnett, C E; Nallani, S C; Rappaport, B A; Throckmorton, D C
- Abstract
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.
- Publication
Clinical pharmacology and therapeutics, 2012, Vol 91, Issue 4, p666
- ISSN
1532-6535
- Publication type
Journal Article
- DOI
10.1038/clpt.2011.273