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© 2012. This work is published under http://creativecommons.org/licenses/by-nc-nd/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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

Details

Title
From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part I–Extrapolation of a Covariate Model From Morphine to Zidovudine
Author
Krekels, EHJ 1 ; Neely, M 2 ; Panoilia, E 3 ; Tibboel, D 4 ; Capparelli, E 5 ; Danhof, M 6 ; Mirochnick, M 7 ; Knibbe, CAJ 8 

 Division of Pharmacology, Leiden, Amsterdam Center for Drug Research, Leiden, The Netherlands; Department of Pediatric Intensive Care and Pediatric Surgery, Erasmus MC‐Sophia Children's Hospital, Intensive Care and Department of Pediatric Surgery, Rotterdam, The Netherlands 
 LAC/USC Medical Center, University of Southern California, LAC/USC Medical Center, Los Angeles, California, USA 
 Division of Pharmacology, Leiden, Amsterdam Center for Drug Research, Leiden, The Netherlands; Laboratory of Pharmacokinetics, University of Patras, Laboratory of Pharmacokinetics, Patras, Greece 
 Department of Pediatric Intensive Care and Pediatric Surgery, Erasmus MC‐Sophia Children's Hospital, Intensive Care and Department of Pediatric Surgery, Rotterdam, The Netherlands 
 Department of Pediatrics, UC San Diego, La Jolla, California, USA 
 Division of Pharmacology, Leiden, Amsterdam Center for Drug Research, Leiden, The Netherlands 
 Division of Neonatology, Boston University, Boston, Massachusetts, USA 
 Division of Pharmacology, Leiden, Amsterdam Center for Drug Research, Leiden, The Netherlands; Department of Pediatric Intensive Care and Pediatric Surgery, Erasmus MC‐Sophia Children's Hospital, Intensive Care and Department of Pediatric Surgery, Rotterdam, The Netherlands; Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands 
Pages
1-9
Section
Original Article
Publication year
2012
Publication date
Oct 2012
Publisher
John Wiley & Sons, Inc.
e-ISSN
21638306
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2299162589
Copyright
© 2012. This work is published under http://creativecommons.org/licenses/by-nc-nd/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.