Tamara van Donge

Chapter 5 82 was 26 – 36 weeks with a median of 32 weeks (Table 1). The median bodyweight was 1.6 kg (0.93 – 2.7 kg). The median PNA was 3 days (0 – 15 days). Of the patients included for analysis 65% were male. The median maternal age was 25.5 years (17 – 34 years). Table 1: Demographic characteristics of study participants included in population PK analysis. Represented as median (min - max) or n [%]. Demographic characteristics of study participants (n=31) Bodyweight (kg) 1.6 (0.93 – 2.7) Gestational age (weeks) 32 (26 – 36) Postnatal age (days) 3 (0 – 15) Post menstrual age (weeks) 32 (26 – 37) Maternal age (years) 25 (17 – 34) Sex Female 10 [32] Male 20 [65] Unknown 1 [3] Structural population pharmacokinetic model A 1-compartment model with first order absorption and elimination kinetics best described the data for (R)- and (S)-methadone (Equation 1 - 3). Log-normal inter-individual variability attributed on both (R)- and (S)- enantiomers and on all parameters significantly improved the model with a fixed inter- individual variability for absorption rate constant of 0.05. The residual variability for methadone of both enantiomers was best described by a proportional error model. Two subjects were excluded from further analysis as they were identified as outliers based on conditional weighted residuals with interaction (CRWESI) versus time diagnostic plots. ! ( ) = − " ! ( ) ! (0) = Equation 1 ( ) = ! " ( ) − # ( ) (0) = 0 Equation 2 ( ) = ( ) ! Equation 3 Covariate models Implementation of bodyweight by allometric scaling (with 0.75 as scaling exponent) did not capture the bodyweight effect on CL (= k e * V d ) and no decline in coefficient of variation for V d and CL was observed. Allometric scaling was therefore not incorporated in the final model. Including GA on CL by a general power function and