The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

Abstract

Background The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg.L−1, while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg.L−1. The racemate of methadone which is commonly used in pediatric and anaesthetic care is metabolized to EDDP (2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine) and EMDP (2-ethyl-5-methyl-3,3-diphenylpyrroline). Methods Data from 4 studies (age 33 weeks PMA-15 years) were pooled (n=56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70 kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n=7) allowed further study of R and S enantiomer pharmacokinetics. Results A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between subject variability) were central volume (V1) 21.5 (29%) L.70kg−1, peripheral volumes of distribution V2 75.1 (23%) L.70kg−1, V3 484 (8%) L.70kg−1, clearance (CL) 9.45 (11%) L.h−1.70kg−1 and inter-compartment clearances Q2 325 (21%) L.h−1.70kg−1, Q3 136 (14%) L.h−1.70kg−1. EDDP formation clearance was 9.1 (11%) L.h−1.70kg−1, formation clearance of EMDP from EDDP 7.4 (63%) L.h−1.70kg−1, elimination clearance of EDDP was 40.9 (26%) L.h−1.70kg−1, and the rate constant for intermediate compartments 2.17 (43%) /h. Conclusions Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg.kg−1 per 8 h in neonates achieves a target concentration of 0.06 mg.L−1 within 36 h. Infusion, rather than intermittent dosing should be considered if this target is to be achieved in older children after cardiac surgery.

Effects of Methadone on Corrected Q-T Interval Prolongation in Critically Ill Children

“…5,6 In a study of intravenous methadone in 7 neonates between 33 and 45 weeks postmenstrual age, the maximum QTc interval prolongation was 10.4 msec; however, all QTc intervals remained within the normal range. 12 In 2 pediatric patients (ages 11 and 17 years) receiving methadone for chronic pain, 1 had no change in QTc interval and the other had QTc prolongation in the setting of concomitant QTc-prolonging drugs. 7 In a recent retrospective review of 37 children with cancer-related pain, the mean QTc during methadone treatment was longer than at baseline (447 vs. 437 msec, respectively).…”

“…11 Furthermore, critically ill children are likely to receive other QTc-prolonging drugs, have electrolyte derangements, and have end-organ dysfunction known to be associated with increased risk for QTc prolongation. [12][13][14][15][16][17] Because methadone administration is prevalent in pediatric intensive care units, we must ensure that existing clinical practice of methadone administration does not cause undue, life-threatening harm. Therefore, we aimed to determine the effects of methadone initiation on QTc interval in critically ill children, including those with underlying cardiac disease.…”

Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant

“…The inter-individual pharmacokinetic variability in adults and children is high. 38–40 A recently completed but unpublished clinical trial investigating oral methadone pharmacokinetics (NCT01754324) confirmed significant variability in response in NAS patients (Personal communication J Wiles). There are significant variations in dosing regimens used.…”

“…Similarly, no QT prolongation in methadone treated neonates has been noted nor has there has been documented morbidity in infants treated for NAS. 40 …”

Pediatric Cardiac Intensive Care Society 2014 Consensus Statement

“…Methadone is equipotent to morphine, but has a much longer peak onset of action (1-2 hr) and half-life (19 hr) (20,23). Methadone is hepatically metabolized by the CYP system to an inactive metabolite, so caution should be used in neonates and very young infants (37). Methadone has been associated with bradycardia, hypotension, and cardiac arrhythmias.…”