Tamara van Donge

Chapter 5 86 Table 3: Percentage of preterm neonates reaching target exposure of 985 mcg∙h/L (cumulative area under the curve) after applying various dosing scenarios according to Table 2. Day 8 was chosen as cut-off due to the length of dosing recommendation published by Wiles et al. . 15 Dosing protocol Percentage reaching target exposure Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 1-8 Days 8-14 Days 14-21 Days 21-28 Scenario 1a 5 59 89 97 99 100 100 100 100 70 37 17 Scenario 1b 8 80 96 99 100 100 100 100 100 74 42 21 Scenario 1c 34 90 98 100 100 100 100 100 100 76 46 24 Scenario 2 5 62 91 97 99 100 100 100 100 64 33 14 Scenario 3 5 62 91 97 99 100 100 100 100 56 27 11 Scenario 4 34 91 99 100 100 100 100 100 100 68 40 20 Discussion This is the first clinical investigation that describes the PK of a single dose of oral methadone in preterm neonates using a quantitative approach for both enantiomers. We found that the clearance of methadone increases with advancing GA and differs slightly between R- and S-enantiomer, being slightly higher for the former (Figure 2). The CL of (R)-methadone in preterm neonates shows a five-fold increase between gestational weeks 26 and 36 (0.0997 - 0.5574 L/h). For (S)-methadone, the CL values increase from 0.0692 to 0.3708 L/h in these preterm neonates. The disposition of methadone is influenced by its chirality, and the volume of distribution for (R)-methadone appears to be higher than for (S)-methadone (26.9 vs 18 L), which is in correspondence with other studies in (term) neonates and in adults. 17,29-31 A previously published study reported clearance values for term neonates after multiple dosing of oral methadone of 8.94 L/h/70 kg. 15 In addition, Ward et al. investigated the pharmacokinetics of methadone and its metabolites after intravenous administration and demonstrated formation CL values of 7.25 and 8.19 L/h/70 kg for R- and (S)-methadone to its corresponding metabolites, respectively. 29 In addition, CL of the methadone metabolites is described by 18.3 and 15.3 L/h/70kg for R- and S-enantiomer, respectively. Converting our retrieved CL values to comparable units, we obtain 10.67 and 7.31 L/h/70 kg for (R)- and (S)- methadone, respectively. Variations in CL values can be observed and might be a possible result of the distinctive investigated populations and their corresponding variability (term versus preterm neonates) and variations in route of administration (intravenous versus oral).