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 and Systems Pharmacology
Department of Pediatric Surgery

Krekels, E., Neely, M. N., Panoilia, E., Tibboel, D., Capparelli, E., Danhof, M., … Knibbe, C. (2012). From pediatric covariate model to semiphysiological function for maturation: Part I-extrapolation of a covariate model from morphine to zidovudine. CPT: Pharmacometrics and Systems Pharmacology, 1(1). doi:10.1038/psp.2012.11