Pharmacometric Evaluation of Umbilical Cord Blood Concentration-Based Early Initiation of Treatment in Methadone-Exposed Preterm Neonates

Abstract

In methadone-exposed preterm neonates, early identification of those at risk of severe neonatal abstinence syndrome (NAS) and use of a methadone dosing regimen that can provide effective and safe drug exposure are two important aspects of optimal care. To this end, we reviewed 17 methadone dosing recommendations in the international guidelines and literature and explored their variability in key dosing strategies. We selected three of the reviewed dosing regimens for their pharmacokinetics (PK) characteristics and their exposure-response relationship in three gestational age groups of preterm neonates (28, 32 and 36 gestational age weeks) at risk for development of severe NAS (defined as an umbilical cord methadone concentration of ≤60 ng/mL, following fetal exposure). We applied early (12 h after birth) vs. typical (36 h after birth) initiation of treatment. We observed that use of universally recommended dosing regimens in preterm neonates can result in under- or over-exposure. Use of a PK-guided dosing regimen resulted in effective target exposures within 24 h after birth with early initiation of treatment (12 h after birth). Future prospective studies should explore the incorporation of umbilical cord methadone concentrations for early identification of preterm neonates at risk of developing severe NAS and investigate the use of a PK-guided methadone dosing regimen, so that treatment failure, prolonged length of stay and opioid over-exposure can be avoided.

Keywords: dosing; methadone; neonatal abstinence syndrome; preterm neonate.

Figure 1

Median predicted methadone concentration (ng/mL) for three typical preterm neonates of 28, 32 and 36 weeks, applying three methadone dosing regimens. Median predicted methadone concentration-time profile for a typical preterm neonate of 32 weeks not receiving methadone treatment is shown in the straight grey line. GA gestational age.