Tamara van Donge

Simplification of methadone dosing in preterm neonates 87 5 Research has shown that CYP2B6 activity increases through infancy and by age of one year CYP2B6 levels and activity reached those of adults. This is also supported by the substrate efavirenz which showed an increase in clearance with body weight and age, reaching 90% of its mature level by 9 months. 32-34 This study showed that clearance of methadone increases with advancing gestational age although the variability of methadone disposition cannot be completely explained by this age effect. Unexplained variability can be a result of e.g. genetic differences in drug transport or in neonatal drug metabolism. 35 Extended research has been performed on genetic variants (polymorphisms) of the major drug metabolizing enzyme, CYP2B6. 18,36 Polymorphisms of the CYP2B6 enzyme alters the disposition of methadone and influences the plasma concentrations, with greater influence for oral administration compared to intravenous administration. 36 CYP2B6*6 allele carriers, particularly homozygous, were observed to have higher methadone concentrations and decreased elimination, while CYP2B6*4 carriers had lower concentrations and increased elimination. 37 CYP2B6*5 appeared not to alter methadone concentrations, although it has to be noted that few subjects were studied. 36 In addition to polymorphisms, other factors might have an impact on the disposition of methadone in preterm neonates, for instance the influence of a combination of maternal drugs, whether the neonate is fed by breastfeeding, and the pH of the urine of the neonate. Although it has been shown that methadone is transferred to neonates through breastfeeding, the absolute amount is small (< 0.2 mg∙day -1 ). 38 In addition, the number of women in methadone programs who breastfeed their newborn has been low and more than half of them discontinue breastfeeding after six days. 39 However, a pharmacodynamic effect has been observed as breastfed neonates have a decreased severity of NAS. It can be argued whether this effect is caused by a very small amount of methadone, or because of the calming and nursing effect of breastfeeding. 14,40 In addition, a study has shown that urine pH has a significant effect on the renal clearance of methadone, although methadone is a lipid soluble basic drug with a pKa of 9.2 and elimination is mostly due to hepatic metabolism. 17,31 When urine pH is 5.2 (acidic), the contribution of renal clearance becomes significant and accounts for around 30% of the total body clearance. When urine pH >7, renal clearance can be neglected from the total body clearance of methadone. 31,41 Extremely low birth weight neonates showed higher urine pH values compared to <1500 gram birth weight infants, indicating the possible lesser extent of renal clearance of methadone clearance in extremely low birth neonates. 42 Therefore, renal clearance may only become of quantitative importance when the urinary pH is below 6. 41 In order to obtain a transparent insights additional studies need to be performed and it is of relevance to collect information on the following aspects; plasma and urine samples of methadone and its two metabolites (EDDP and EDMP)