title: From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II-Sensitivity to Physiological and Physicochemical Properties.
abstract: To develop a maturation function for drug glucuronidation in children, that can be used in population and physiologically based modeling approaches, the physiological and physicochemical basis of a semiphysiological glucuronidation function for children was untangled using Simcyp. The results show that using the currently available in vitro data, in vivo morphine and zidovudine clearances were under predicted by the physiologically based model in Simcyp. The maturation profile was similar to the clinically observed profile except for the first 2 weeks of life, and liver size and UGT2B7 ontogeny are the physiological drivers of the maturation of glucuronidation. Physicochemical drug parameters did not affect this maturation profile, although log P and pKa influenced the absolute value of clearance. The results suggest that the semiphysiological glucuronidation function for young children can be used to predict the developmental clearance profile of other UGT2B7 substrates, though scenarios with nonlinear kinetics and high-extraction ratios require further investigation.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e10; doi:10.1038/psp.2012.12; advance online publication 10 October 2012.
authors.affiliation: 1] Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands [2] Department of Pediatric Intensive Care and Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: E H J
authors.initials: EH
authors.lastname: Krekels
authors.forename: T N
authors.initials: TN
authors.lastname: Johnson
authors.forename: S M
authors.initials: SM
authors.lastname: den Hoedt
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: D
authors.initials: D
authors.lastname: Tibboel
authors.forename: C A J
authors.initials: CA
authors.lastname: Knibbe