Population Pharmacokinetics to Support Intravenous and Enteral Methadone Dosing in Children
01/2026
Journal Article
Authors:
Watt, K. M.;
Thompson, E. J. ;
Lam, L.;
Zimmerman, K.;
Hornik, C. P.;
Atz, A. M.;
Fernandez, A.;
Hupp, S. R.;
Bhatt-Mehta, V.;
Benjamin, D. K., Jr.;
Anand, R.;
Cohen-Wolkowiez, M.;
Gonzalez, D.;
Smith, P. B. ;
Capparelli, E. V.;
Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering, Committee
Volume:
66
Issue:
1
Journal:
J Clin Pharmacol
PMID:
41474167
URL:
https://www.ncbi.nlm.nih.gov/pubmed/41474167
Keywords:
Humans *Methadone/pharmacokinetics/administration & dosage/blood Male Child Child, Preschool Female Adolescent Infant *Analgesics, Opioid/pharmacokinetics/administration & dosage/blood Prospective Studies
Administration, Intravenous Young Adult Models, Biological Bayes Theorem Half-Life children dosing methadone obesity pharmacokinetics
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.