Methadone dosing strategies in preterm neonates can be simplified

Abstract

Aims: A dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics (PK) of methadone is available in preterm neonates. Therefore we investigated developmental PK of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population.

Methods: A single-centre open-label prospective study was performed to collect PK data after a single oral dose of methadone in preterm neonates. A population PK model was built to characterize developmental PK of (R)- and (S)-methadone. Model-based simulations were performed to identify a simplified dosing strategy to reach and maintain target methadone exposure.

Results: A total of 121 methadone concentrations were collected from 31 preterm neonates. A one-compartment model with first order absorption and elimination kinetics best described PK data for (R)- and (S)-methadone. Clearance increases with advancing gestational age and differs between R- and S-enantiomer, being slightly higher for the former (0.244 vs 0.167 L/h). Preterm neonates reached target exposure after 48 hours with currently used dosing schedules. Output from simulations revealed that target exposures can be achieved with a simplified dosing strategy during the first 4 days of treatment.

Conclusion: Methadone clearance in preterm neonates increases with advancing gestational age and its disposition is influenced by its chirality. Simulations that account for developmental PK changes indicate a shorter methadone dosing strategy can maintain target exposure to control withdrawal symptoms.

Trial registration: ClinicalTrials.gov NCT01327079.

Keywords: dosing optimization; gestational age; methadone; neonatal abstinence syndrome; preterm neonates.

Conflict of interest statement

M.P. has part‐time employment with the consulting company Certara, USA.

© 2019 The British Pharmacological Society.

Figures

Figure 1

Observed plasma concentrations versus time after single oral dose of methadone. Smoothed conditioned means for (R)‐methadone and (S)‐methadone are presented by dotted and solid lines, respectively

Figure 2

(R)/(S)‐methadone clearance values for different weeks of gestational age. (R)‐methadone and (S)‐methadone values are presented by open and black circles, respectively. Medians for (R)‐methadone and (S)‐methadone clearance are presented by dotted and solid lines, respectively. Prediction intervals (95%) are obtained by model‐based simulations based on all included subjects and presented for (R)‐ and (S)‐methadone

Figure 3

Simulated (R)/(S)‐methadone concentrations over nine days according to dosing Scenarios 1a and 3. Medians for (R)/(S)‐methadone concentrations are presented by black lines, respectively. Prediction intervals (95%) are obtained by model‐based simulations based on all included subjects and presented for (R)‐ and (S)‐methadone