Tamara van Donge

Simplification of methadone dosing in preterm neonates 81 5 Dataset analysis and population pharmacokinetics Dataset analysis Sixty patients were included in the study after given informed consent. Fifty-three of them were included in the data-analysis after exclusion of pre-dose measurements (N=57, 12%) and LLOQ data (N=35, 19%). Based on an exploratory analysis of the PK data and prior knowledge of the PK physicochemical properties of methadone, the following exclusion criteria were applied; patients with less than three measurements, patients with an unexpected increase of 30% in the elimination phase and patients with t max (time point at which maximum concentration is reached) after 48 hours were excluded from further analysis. In total, 31 patients with 121 (R)- and (S)-methadone plasma levels were included in the analysis dataset for the development of the population PK model. 0 5 10 15 0 20 40 60 Time after dose (hr) R/S Methadone concentration (mcg/L) R−methadone S−methadone Figure 1: Observed plasma concentrations versus time after single oral dose of methadone. Smoothed conditioned means for (R)-methadone and (S)-methadone are presented by solid lines in blue and green, respectively. Plasma concentrations of (R)- and (S)-methadone were highly variable, with a range of 0.251 – 15.49 mcg/L (Figure 1). Measurements were taken over a period of 72 hours. Neonates included for the population PK analysis were considered preterm as the overall GA range