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CPT Pharmacometrics Syst Pharmacol. 2012 Oct 3;1:e9. doi: 10.1038/psp.2012.11.

From pediatric covariate model to semiphysiological function for maturation: part I-extrapolation of a covariate model from morphine to Zidovudine.

Author information

1
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, Intensive Care and Department of Pediatric Surgery, Rotterdam, The Netherlands.

Abstract

New approaches to expedite the development of safe and effective pediatric dosing regimens and first-in-child doses are urgently needed. Model-based approaches require quantitative functions on the maturation of different metabolic pathways. In this study, we directly incorporated a pediatric covariate model for the glucuronidation of morphine into a pediatric population model for zidovudine glucuronidation. This model was compared with a reference model that gave the statistically best description of the data. Both models had adequate goodness-of-fit plots and normalized prediction distribution errors (NPDE), similar population clearance values for each individual, and a Δobjective function value of 13 points (Δ2df). This supports our hypothesis that pediatric pharmacokinetic covariate models contain system-specific information that can be used as semiphysiological functions in pediatric population models. Further research should explore the validity of the semiphysiological function for other UDP-glucuronosyltransferase 2B7 substrates and patient populations and reveal how this function can be used for pediatric physiologically based pharmacokinetic models.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e9; doi:10.1038/psp.2012.11; advance online publication 3 October 2012.

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