Open AccessFrom Pediatric Covariate Model to Semiphysiological Function for Maturation: Part I–Extrapolation of a Covariate Model From Morphine to Zidovudine
Author(s) -
Krekels EHJ,
Neely M,
Panoilia E,
Tibboel D,
Capparelli E,
Danhof M,
Mirochnick M,
Knibbe CAJ
Publication year - 2012
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1038/psp.2012.11
Subject(s) - covariate , glucuronidation , nonmem , population , dosing , medicine , pharmacology , econometrics , statistics , biology , mathematics , biochemistry , environmental health , enzyme , microsome
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