title: A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients.
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.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Florian
authors.forename: C E
authors.initials: CE
authors.lastname: Garnett
authors.forename: S C
authors.initials: SC
authors.lastname: Nallani
authors.forename: B A
authors.initials: BA
authors.lastname: Rappaport
authors.forename: D C
authors.initials: DC
authors.lastname: Throckmorton
mesh_terms: D000328:Adult; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000097:blood / Q000139:chemically induced*; D008297:Male; D008691:Methadone / Q000009:adverse effects* / Q000097:blood; D008875:Middle Aged; D008954:Models, Biological; D009293:Opioid-Related Disorders / Q000097:blood / Q000188:drug therapy*; D011446:Prospective Studies
chemical_list: D008691:Methadone