Tamara van Donge

Simplification of methadone dosing in preterm neonates 85 5 0 20 40 60 80 Scenario 1a time10c 0 20 40 60 80 0 24 48 72 96 120 144 168 192 216 Time (hr) Scenario 3 R/S−methadone concentration (mcg/L) Figure 3: Simulated (R)/(S)-methadone concentrations over nine days according to dosing Scenario 1a and Scenario 3. Medians for (R)/(S)-methadone concentrations are presented by black lines, respectively. Prediction intervals (95%) are obtained by model-based simulations based on all included subjects and presented for (R)- and (S)-methadone. It can be observed that after administering methadone according to Scenario 3, methadone concentrations decrease slightly more rapid compared to the weaning regimen as suggested in Scenario 1a, despite the fact that both dosing scenarios achieve similar percentages (59% and 62%) of patients reaching target concentrations after 48 hours (Table 3). It is demonstrated that the target AUC of 985 mcg∙h/L is reached in approximately 60% of patients after 48 hours for Scenario 1a, 2 and 3, whereas it has been shown that this target exposure is reached after 24 hours for term neonatal patients. 15 Considering Scenario 1c and Scenario 4, where the loading dose is increased by two-fold (0.2 mg∙kg -1 ) in the first 24 hours, approximately 90% of patients are expected to achieve target exposure after 48 hours (Table 3). In addition, it is observed that a large number of patients (70%) is still above target level even after 14 days, although methadone administration has been stopped at day 8 (Scenario 1a). When the tapering dosing regimen is stopped after 4 days (Scenario 3), 56% of patients maintain an effective methadone exposure for 2 weeks after start of treatment.