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

Abstract

Chronic intrauterine exposure to psychoactive drugs often results in neonatal abstinence syndrome (NAS). NAS is the symptomatic drug withdrawal in newborns that generally occurs after in utero chronic opioid exposure. Methadone is an opioid analgesic commonly prescribed for pharmacologic management of NAS. It exhibits high pharmacokinetic (PK) variability. The current study used physiologically based PK modeling to predict the PK profile of methadone in 20 newborns treated for NAS. The physiologically based PK simulations adequately predicted the PK profile of the clinical data for 45% of the patients. Sensitivity analyses were conducted to explore contributing factors to methadone PK variability. The data suggest that P450 enzymatic activity impacts the clearance of methadone in virtual adults and neonates, while the contribution of cardiac output may be negligible. Understanding maturational and/or pharmacogenetic changes in cytochrome P450 enzymatic activity may further explain the large PK variability of methadone in newborns with NAS and will help individualized treatment.

Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches

“…The model was designed to study methadone metabolism and PK during early childhood. An additional study, conducted by our group, 95 used PBPK models to provide mechanistic insight into factors that contribute to the PK variability of R‐ and S‐methadone in NOWS patients. The study incorporated a CYP450 ontogeny function into the neonatal model that was designed for NOWS patients 48 .…”

“…The study incorporated a CYP450 ontogeny function into the neonatal model that was designed for NOWS patients 48 . The simulations suggested that the contribution of enzymatic activity may alter the PK profile of methadone in neonates and in adults 95 . In addition, a study by Johnson et al 96 assessed the maturation of metabolism and elimination in newborn subjects sublingually administered buprenorphine.…”

“…48 The simulations suggested that the contribution of enzymatic activity may alter the PK profile of methadone in neonates and in adults. 95 In addition, a study by Johnson et al 96 assessed the maturation of metabolism and elimination in newborn subjects sublingually administered buprenorphine. The model simulations suggested that the biliary elimination of buprenorphine in neonates at birth may be similar to adult levels.…”

Clinical pharmacology and dosing regimen optimization of neonatal opioid withdrawal syndrome treatments

“…91 Using data from published PK studies in infants and children who received intravenous, rectal, or epidural clonidine (380 observations from 72 subjects, aged 0-14 years), Potts et al 83 reported a population PK model incorporating allometric scaling of PK parameters and asymptotic exponential maturation of clearance based on PNA. A two-compartment model was used for data fitting, and the normalized parameter estimates for 70-kg adults were 14.6 L/h for clearance, 62.5 L for central volume, and 119 L for peripheral volume. These standardized values are close to reported values in adult studies.…”

“…122 The workflow for | 1245 PHARMACOLOGY OF NOWS TREATMENTS developing a pediatric PBPK model starts from development and verification of an adult PBPK model, followed by development and evaluation of a pediatric model 123 ; this workflow was implemented in two example studies with methadone and buprenorphine mentioned earlier in the text. 62,76 The most important prerequisite for reliable translation to pediatrics is knowledge of drug-specific ADME processes in adults and ontogeny of such processes 122 ; therefore, lack of qualified systems data and existing knowledge gap in the rapid physiological changes and maturation of organs/tissues related to drug disposition in neonates is expected to pose challenges to developing robust PBPK models in pediatrics. 119,124 Compared with PKs in pediatrics, there is in general limited information on how developmental changes and their interaction with disease impact PD, and therefore quantifying drug effect in pediatric patients is considered the biggest obstacle.…”