Tamara van Donge

Chapter 5 84 Goodness-of-fit plots for (R)- and (S)-methadone (Figure 1 Supporting Information) demonstrates data points show negligible bias around the line of unity, indicating that the model accurately describes the observations. Considering the conditional weighted residuals with interaction over time after dose, a small bias was retained in the model, which could not be further improved by additional model development. Results obtained from bootstrap analysis are provided in Table 1 Supporting Information. Parameters estimates of the final model are within the 95% CIs and median values are in accordance with final parameter estimates. Additional sensitivity analysis, where patients with 30% increase in elimination phase were included in the final PK model, had minimal impact on the clearance estimates. For a typical patient (32 weeks GA) an increase of 1.9% and 18% of R- and S-methadone clearance was observed, respectively. As these results show minimal influence on the final model estimates, these individuals were not included in analysis dataset. Table 2: Dosing scenarios (in mg∙kg -1 ) applied for methadone simulations. Scenario 1a - 1c are derived and adjusted from Wiles et al.. 15 Scenario 2 - 4 represent simplified dosing strategies. Tapering Scenario 1a Scenario 1b Scenario 1c Scenario 2 Scenario 3 Scenario 4 Frequency Day 1 0.1 0.15 0.2 0.1 0.1 0.2 q6 x 4 Day 2 0.075 0.075 0.075 0.1 0.1 0.1 q12 x 2 Day 3 0.05 0.05 0.05 0.05 0.05 0.05 q12 x 2 Day 4 0.04 0.04 0.04 0.01 0.01 0.01 q12 x 2 Day 5 0.03 0.03 0.03 0.01 - - q12 x 2 Day 6 0.02 0.02 0.02 0.01 - - q12 x 2 Day 7 0.01 0.01 0.01 0.01 - - q12 x 2 Day 8 0.01 0.01 0.01 0.01 - - q24 x 1 Simulations to evaluate methadone dosing recommendations Model-based simulations were performed to investigate the concentration-time profiles of methadone based on different dosing scenarios and the proportion of preterm neonates reaching the methadone target exposure (985 mcg∙h/L) were examined. Multiple dosing scenarios as proposed in Table 2, where the duration of the weaning period and dosage of methadone vary, were applied to all patients included in the study and methadone concentration-time profiles were obtained. Figure 3 represents the R/S-methadone plasma concentrations from 100 simulations with the predicted median and range (5 th and 95 th percentile) for Scenario 1a and 3, respectively.