Tamara van Donge

Chapter 5 88 for a considerate period of time (at least one half-life for metabolites). In addition, the fraction of the enzymatic pathway (due to CYP2B6) and renal excretion can be estimated and investigated. Subsequently, it might be beneficial to collect genetic information concerning the known impact of polymorphisms. Target exposure for the mitigation of withdrawal symptoms was retrieved and applied from earlier research where it was shown that term neonates achieving the target exposure of 985 mcg∙h/L were able to control their withdrawal signals 24 hours after start of treatment. 15 To our knowledge, there is currently no target exposure for preterm neonates available. In addition, it should be recognized that scoring systems for the diagnosis of NAS are generally developed for term neonates, whereas preterm neonates exhibit different signs of withdrawal (e.g. less severe symptoms due to neurologic immaturity). 11 Aforementioned reflects the urge for the development of new scoring systems, especially for preterm neonates. In total, six different dosing scenarios were investigated and the exposure of methadone in preterm neonates were simulated (Table 2). The exposure of methadone (not the dose) generates the pharmacodynamic effect, which in this case is the control of withdrawal symptoms. When applying weaning dosing Scenario 1a the target exposure is reached after 48 hours for 59% of the preterm neonates. Focusing on Scenario 1c where the dosages in the first 24 hours are increased by two-fold ensures that 90% of patients will achieve target AUC exposure after 48 hours, but only 34% reaches this target after 24 hours (Table 3). It can be questioned whether it is harmless to increase the first 4 dosages by two-fold (0.1 mg∙kg -1 to 0.2 mg∙kg -1 q6 x 4) in order to control withdrawal symptoms without jeopardizing safety (Scenario 1c and 4). Although a recent study administered higher methadone dosages, further research should elaborate on this safety concern. 13 When administering methadone for only 4 days (Scenario 3 and 4), still 62% and 91% of preterm neonates will, respectively, achieve target exposure after 48 hours. Focusing on the methadone exposure (cumulative AUC) in the first 8 days after start of treatment, it can be observed that all dosing strategies are capable to achieve effective exposure in all preterm neonates (Table 3). On the other hand, when applying extensive weaning protocols (Scenario 1a, 1b and 1c) it can be observed that approximately 70% of preterm patients still maintain an effective exposure after 8 days of treatment, even though no dosages of methadone are given in this period. To our current knowledge it remains unclear whether this extended and prolonged methadone exposure could have beneficial consequences such as the absence of withdrawal symptoms in the following days (and weeks) although it can be debated whether being exposed to methadone for such a long time could have negative consequences for further development of the preterm neonate (e.g. maturation central nervous system).