Tamara van Donge

Chapter 6 116 Supporting Information 2 - Tables Table S1: Comparison of patient populations used for the development of population PK models for ibuprofen in preterm neonates with PDA. Data presented as median (range). * Depending on PNA. Current study Gregoire et al. 2008 Engbers et al. 2020 Sample size (n) 23 108 67 Postnatal age (days) 3.1 (1.2 – 15.6) 1 (0 – 8) 3 (1 – 12) Gestational age (wks) 25.9 (23.4 – 27.3) 26.9 (24 – 30.7) 26.1 (24 – 30.1) Birth weight (g) 780 (540 – 1150) 880 (300 – 1700) 870 (470 – 1450) Dose schedule (per protocol) 10,5,5 mg/kg and 20,10,10 mg/kg* 10,5,5 mg/kg 10,5,5 mg/kg TableS2: PopulationPK parameter estimates for S- andR-ibuprofen. Covariate parameter relationships: ( ) = ( ) × . . × . . . ( ) = ( ) + . × ( − . ). = × . . Ka: absorption rate constant, Vd: volume of distribution, F: bioavailability, CL: Clearance, PNA: postnatal age, GA: gestational age, SGA: small for GA, WT: weight, RSE: residual standard error, IIV: inter-individual variability, CV: coefficient of variation, a : parameter where prior information is used. Parameter (unit) S-ibuprofen R-ibuprofen Population parameters Estimate (RSE%) Estimate (RSE%) Ka (/h) 0.095 (7.8%) 0.162 (0.9%) Vd/F (L) 0.119 a (39.4%) 0.431 a (4.8%) CL/F (L/h) 0.0057 (5.9%) 0.074 (3.9%) Covariate parameters Estimate (RSE%) Estimate (RSE%) PNA effect on CL 1.15 (42.7%) 11.7 (1.6%) GA effect on CL 6.91 (15.3%) - WT effect on Vd 0.792 (32.5%) 0.792 (32.5%) Inter-individual variability IIV (CV%) IIV (CV%) Vd/F 0.088 a (30.4%) - CL/F 0.218 a (49.3%) - Residual variability Proportional error 0.08 0.98 Additive error 16.3 0.38