Salivary therapeutic monitoring of methadone toxicity in neonates after transplacental transfer from parturient mothers treated with oral methadone guided by PBPK modeling

Opioid use disorders (OUD) during pregnancy are related to neonatal opioid withdrawal syndrome (NOWS). R,S-methadone used to treat OUD and NOWS can penetrate the placenta. High neonatal brain extracellular fluid (bECF) levels of R,S-methadone can induce respiratory depression in newborns. The purpose of this work was to estimate neonatal bECF and saliva levels to establish the neonatal R,S-methadone salivary thresholds for respiratory depression after maternal oral dosing despite the sparse data in pregnancy and newborn populations. An adult physiologically-based pharmacokinetic (PBPK) model for R,S-methadone after intravenous and oral administration was constructed, vetted, and scaled to newborn and pregnancy populations. The pregnancy model predicted the R-methadone and S-methadone doses transplacentally transferred to newborns. Then, the newborn PBPK model was used to estimate newborn exposure after such doses. After maternal oral dosing of R,S-methadone (43.8 mg/day), the neonatal plasma levels were below the respiratory depression threshold. Further, the bECF levels were above the analgesia threshold for more than 96 h. The salivary thresholds for the analgesic effects of R-methadone, S-methadone, and R,S-methadone were estimated herein at 1.7, 43, and 16 ng/mL, respectively. Moreover, the salivary thresholds for the respiratory depression of R-methadone and R,S-methadone were estimated at 58 and 173 ng/mL, respectively. Using neonatal salivary monitoring of methadone can be useful in ensuring newborns' safety during maternal OUD treatment.