Tamara van Donge

Chapter 7 132 Figure 1: Observed serum creatinine (Scr) concentrations versus postmenstrual age (gestational age (GA) + postnatal age), grouped per GA category. The initial condition at time zero was estimated with the parameter Crea birth , which represents creatinine concentration at birth (Equation 2). Input and output rates were defined as the production rate of creatinine (kin production , mg/day) and time varying rate constant of creatinine elimination (kou(t) elimination , day -1 ), which was parameterized in terms of time-dependent creatinine clearance (CL(t), L/day) and weight-normalized Vd (Equation 3, 4). Where t is the time after birth, i.e. postnatal age (day), CL BL corresponds to the baseline creatinine clearance (L/day), emax is the maximum additional achieved clearance (L/day), t 50 reflects the time point (day) where half of emax is achieved (which may be partly interpreted as time point at which creatinine reabsorption decreased by 50%) and the Hill coefficient determines the steepness of the clearance- time relationship. To illustrate the driving force of Scr profiles (Scr production versus elimination), the ratio of the amount of creatinine produced (kin production ) versus the amount eliminated (kou(t) elimination x Scr(t)) was calculated for each time point. Sensitivity analysis of Vd did not show substantial bias in estimation of the key population parameters, as the percentage difference between 0.7 L/kg and varying Vds did not exceed 5%, with exception for two population parameters (kin production and emax,