Abstract
Methadone is used in hospitalized children to treat pain and iatrogenic opiate withdrawal. Optimal pediatric dosing for both enteral and intravenous methadone is unknown. We conducted two prospective, multi-center, open-label studies to characterize the pharmacokinetics of methadone in the pediatric population. These studies were conducted at a total of 23 US children's hospitals. Ninety-nine children with a median (range) age of 2.3 (0-19.0) years and weight of 13.0 (0.72-159) kg were prescribed methadone per standard of care for treatment of pain or iatrogenic opiate withdrawal. Ninety-nine children received median (range) methadone doses of 0.11 (0.01-0.39) mg/kg intravenously and 0.10 (0.01-0.61) mg/kg enterally. Ten participants received only intravenous doses; 78 received only enteral doses; and 11 received intravenous and enteral doses. We analyzed 263 pharmacokinetic samples with a median (range) methadone plasma concentration of 42.2 (0.9-729.2) ng/mL. A one-compartment population pharmacokinetic model described the methadone data well. Median (range) empiric Bayesian estimates of clearance, volume of distribution, and half-life were 0.17 (0.009-1.50) L/h/kg, 4.99 (0.97-20.6) L/kg, and 20.5 (3.0-86.2) h, respectively. Dosing simulations showed that doses of 0.1 mg/kg every 8 h (intravenous) and 0.2 mg/kg every 8 h (enteral) achieved exposures associated with pain control and reduction in withdrawal symptoms. Based on observed exposures and model simulations, we recommend a starting dose of 0.1 mg/kg intravenous or 0.2 mg/kg enterally (max 10 mg) every 8 h. Because of wide interindividual variability, this dose should be titrated to effect.