Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study

Abstract

Objective To characterize the population pharmacokinetic (PK) of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome (NAS) and to develop a PK model towards an evidence-based treatment protocol. Study design Based on a methadone dosing protocol, serum concentrations of methadone and its metabolites were assessed via 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 inter-individual variability in methadone concentrations. Blood concentrations of methadone were best described by a one-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 NAS 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. Trial registration ClinicalTrials.gov: NCT01754324

Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients

“…Simulations were conducted with a nominal dose but not the actual dose, which may result in an overprediction of the clinical data. Also, drug screens and/or maternal reporting revealed that 60% of the newborns were exposed to multiple opioids and 40% were exposed to opioids plus additional substances of abuse (ie, cocaine, marijuana, benzodiazepines) in utero . Fetal exposure to certain compounds have been shown to alter organ function, thereby potentially altering methadone concentrations .…”

“…The blood‐to‐plasma ratio in neonates was estimated based on the fixed adult erythrocyte‐to‐plasma ratio and neonatal hematocrit values (), as described in the Supplementary Material S1 of Emoto et al These parameters are summarized in Table . The pharmacokinetic profiles of R‐ and S‐methadone were simulated according to the actual dosing regimen for each of the 20 full‐term newborns with no known compromising illnesses treated for NAS, and then the simulated results were compared to the time‐course concentration data observed in the PK study in newborns with NAS . The sum of R‐ and S‐methadone AUC was used to predict the performance of the simulations.…”

“…Clinical data and demographic information for each newborn with NAS were obtained from a previous study conducted at the University of Cincinnati Medical Center . For the purposes of the study, the frequency of obstetric care provided prior to delivery was quantified based on prenatal records available in the electronic medical records.…”

“…The study created a stepwise dosing protocol that decreases the amount of methadone administered based on the pharmacodynamics (ie, Finnegan score) of the newborn until weaning was achieved. Adoption of the treatment protocol proposed from the study resulted in a decrease in the duration of methadone weaning and in shortened hospital lengths of stay . The dosing regimen is endorsed by the Ohio Perinatal Quality Collaborative as a NAS treatment option for the state of Ohio.…”

The Triple Aim for Neonatal Abstinence Syndrome

“…In this issue of The Journal , Wiles et al 3 provide initial pharmacokinetic data for oral methadone use in infants with NAS. The literature supports the use of an opioid to treat opioid withdrawal 4 ; however, data supporting one treatment protocol over another are lacking.…”