Tamara van Donge

Simplification of methadone dosing in preterm neonates 89 5 We have shown that 62% of neonates reaches target methadone exposure after 48 hours after start of treatment when applying Scenario 3. Additionally, we have observed that a dosing regimen of 4 days maintains effective target attainment in the first week of treatment. Applying such a simplified, but still efficacious dosing strategy has numerous advantages such as fewer interventions for the patient and reduced risk of administration errors related to complex dosing schedules. In addition, it should also be recognized that shortened treatment of methadone could have a positive impact on likelihood of opioid dependence. Possible reason that methadone requires less frequent dosing in preterm could be explained by the relatively long half-life. In this analysis it is assumed that the target exposure remains the same over the entire period. It can be hypothesized that the target exposure fluctuates over time because of developing physiology; further research is required to clarify this assumption. This clinical investigation demonstrates that the clearance of methadone increases with advancing gestational age and higher clearance values and volumes of distribution can be observed for (R)-methadone as compared to (S)-methadone in preterm neonates. Simulations that account for developmental pharmacokinetics indicate that current complex dosing schemes might be replaced by a simplified and shortened dosing strategy. Such dosing strategy will not only reduce the risk of measurement errors related to complex dosing schedules, but also lowers the number of interventions in these preterm patients. Additional clinical studies are warranted to better understand different metabolites of methadone, investigate genetic variants of the relevant drug metabolizing enzymes such as CYP2B6, and evaluate clinical benefits of a simplified methadone dosing strategy in preterm neonates.