Tamara van Donge (1), Samira Samiee-Zafarghandy (2), Marc Pfister (1,3), Gilbert Koch (1), Majid Kalani (4), Arash Bordbar (4), John van den Anker (1,5,6)
(1) Pediatric Pharmacology and Pharmacometrics, University Children`s Hospital Basel, University of Basel, Basel, Switzerland, (2) Department of Pediatrics, Division of Neonatology, McMaster University, Ontario, Canada, (3) Certara LP, Princeton, NJ, USA, (4) Department of Pediatrics, Shahid Akbarabadi Hospital, Iran University of Medical Sciences, Tehran, Iran, (5) Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children`s Hospital, Rotterdam, The Netherlands, (6) Division of Clinical Pharmacology, Children`s National Health System, Washington, DC, USA
Introduction: 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 [1]. Despite its abundant use, hardly any data on the pharmacokinetics (PK) of methadone is available in preterm neonates. Therefore we characterized the developmental pharmacokinetics of methadone using population PK modeling and evaluated current dosing strategies and possible simplification in this vulnerable population.
Methods: A single center open-label prospective study was performed to collect PK data in preterm neonates after a single oral dose of 0.1 mg/kg of methadone was administered. A population PK model was built to characterize developmental PK of (R)- and (S)-methadone. Exponential, power and linear model functions were tested to describe covariate effects of continuous variables such as weight and age variables. Model-based simulations were performed to examine the feasibility of a simplified dosing strategy to achieve and maintain target methadone exposure. Methadone target exposure (985 mcg∙h/L) was retrieved from an earlier study conducted in term neonates [2].
Results: A total of 121 methadone concentrations were collected from 31 preterm neonates, with overall gestational age range of 26 – 36 weeks with a median of 32 weeks. A one-compartment model with first order absorption and elimination kinetics best described PK data for (R)- and (S)-methadone, including gestational age on clearance by a general power function and on volume of distribution in a linear relationship. The exponents of the effect of gestational age on clearance of methadone were comparable between the two enantiomers (5.29 for (R)-methadone and 5.16 for (S)-methadone). The clearance of methadone increases with increasing gestational age and differs between R- and S-enantiomer, being slightly higher for the former (0.244 versus 0.167 L/h). The population parameter values for apparent volume of distribution for (R)- and (S)-methadone corresponded to 26.9 L and 18 L, respectively. Preterm neonates reached target exposure after 48 hours with currently used dosing schedules. Currently used dosing schedules consist of a weaning period (one week) with starting dose of 0.1 mg/kg and daily dose adjustments of 0.025 or 0.01 mg/kg. Output from simulations revealed that target exposures can be achieved and maintained with a simplified dosing strategy during four days of treatment (starting with 0.1 mg/kg on day 1 and 2, 0.05 mg/kg on day 3 and 0.01 mg/kg on day 4). It is therefore questionable if there is a need for the currently used complex dosing regimen of methadone in neonates.
Conclusion: Clearance of methadone in preterm neonates increases with increasing gestational age and higher clearance values and volumes of distribution can be observed for (R)-methadone as compared to (S)-methadone. Simulations that account for developmental PK changes indicate that a simplified, shorter methadone dosing strategy can maintain target exposure to control withdrawal symptoms in preterm neonates. Such dosing strategy will not only reduce the risk of measurements errors related to complex dosing schedules, but also lowers the number of interventions in these preterm patients.
References:
[1] Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal Abstinence Syndrome and Associated Health Care Expenditures: United States, 2000-2009. JAMA. 2012;307(18):1934–1940. doi:10.1001/jama.2012.3951
[2] Wiles JR, Isemann B, Mizuno T, et al. Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study. J Pediatr. 2015;167(6):1214-20.e3.
Reference: PAGE 28 (2019) Abstr 8868 [www.page-meeting.org/?abstract=8868]
Poster: Drug/Disease Modelling - Paediatrics