title: Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome and to develop a pharmacokinetic (PK) model toward an evidence-based treatment protocol.
  
  
  METHODS
  Based on a methadone dosing protocol, serum concentrations of methadone and its metabolites were assessed by high performance liquid chromatography-tandem mass spectrometry from dried blood spots. Population PK analysis was performed to determine the volume of distribution and clearance of oral methadone. Methadone plasma concentration-time profiles were simulated from the deduced PK model to optimize the dosing regimen.
  
  
  RESULTS
  There was substantial interindividual variability in methadone concentrations. Blood concentrations of methadone were best described by a 1-compartment model with first-order absorption. The population mean estimates (coefficient of variation percentage) for oral clearance and volume of distribution were 8.94 (103%) L/h/70 kg and 177 (133%) L/70 kg, respectively. Optimized dosing strategies were developed based on the simulated PK profiles. We suggest a starting dose of 0.1 mg/kg per dose every 6 hours for most patients requiring pharmacologic treatment of neonatal abstinence syndrome followed by an expedited weaning phase.
  
  
  CONCLUSIONS
  The proposed dosing regimen may reduce the cumulative dose of opioid and shorten the length of hospitalization. Future studies should aim to validate the simulated dosing schemes with clinical data and expand our understanding of the between-patient PK variability.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01754324.
authors.affiliation: Perinatal Institute, Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Wiles
authors.affiliation: Department of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH.
authors.forename: Barbara
authors.initials: B
authors.lastname: Isemann
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Tabangin
authors.affiliation: Perinatal Institute, Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Ward
authors.affiliation: Perinatal Institute, Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Henry
authors.initials: H
authors.lastname: Akinbi
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. Electronic address: sander.vinks@cchmc.org.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002853:Chromatography, Liquid; D006801:Humans; D007231:Infant, Newborn; D013058:Mass Spectrometry; D008691:Methadone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008954:Models, Biological; D009357:Neonatal Abstinence Syndrome / Q000188:drug therapy*; D010865:Pilot Projects
chemical_list: D000701:Analgesics, Opioid; D008691:Methadone