Tamara van Donge

Chapter 5 78 subjective. 8,9 In addition, these scoring systems are generally developed for term neonates, whereas preterm neonates exhibit different signs of withdrawal and, for instance, less severe symptoms of withdrawal may be observed due to neurologic immaturity. 10,11 As a result, these scoring systems might under- or over-predict the severity of NAS. Opiates such as methadone and morphine belong to the first-line treatment for neonates with NAS. 10,12 A recent study has shown that short-term outcomes were better in infants who were treated with methadone as compared to morphine. 13 Although no universally accepted treatment protocol exists, methadone dosage is tapered gradually to help wean the neonate of the drug once the signs of withdrawal are under control. As a consequence, current dosing recommendations for methadone are often quite complex and require a taper or weaning period. 11,14,15 Despite the abundant use of methadone there is very little data on the pharmacokinetics (PK) of this drug is available in preterm neonates. Methadone is a racemic stereoselective opioid agonist with a relative long half- life of approximately 25-32 hours and is mainly converted by hepatic metabolism via N-demethylation to the inactive metabolite 2-ethylidene-1,5-dimethyl-3,3- diphenylpyrrolidine (EDDP) and subsequently to 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). 10,16 Methadone is administered as a racemic mixture of (R)- and (S)-methadone, although the former enantiomer accounts for most opioid effects and is highly bound to plasma proteins, α 1 -acid glycoprotein being the most relevant one. 17 The enzymes that metabolize methadone has been extensively studied by Kharasch et al. and although the metabolism has been attributed to cytochrome P450 3A4 (CYP3A4) for many years, it was found that CYP2B6 is the major enzyme responsible for the biotransformation of methadone and that CYP3A4 only plays a minor role in methadone N-demethylation. 16,18 The activity of CYP2B6 varies significantly among individuals, and neonates present complex and unpredictable maturation profiles of drug-metabolizing enzymes (DMEs). 19 These enzymes do not develop with the same rates and can be altered by the in utero exposure of maternal drugs. Although the PK profiles of oral and intravenous methadone have been described for adults receiving methadone as treatment for opioid dependence, these profiles cannot simply be extrapolated to preterm neonates. 20-22 Today, the paucity of information concerning the developmental aspects on the exposure of methadone in preterm neonates highlights the need for additional studies to investigate the complex pharmacology of methadone and its large inter-individual variability in PK. 10,15,16 This study aimed at (i) characterizing the PK of oral methadone in preterm neonates using population PK modeling, (ii) assessing the influence of demographic characteristics on PK parameters, and (iii) evaluating current dosing strategies and target exposure.