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.

Additional Metadata
Persistent URL dx.doi.org/10.1038/psp.2012.11, hdl.handle.net/1765/57770
Journal CPT: Pharmacometrics and Systems Pharmacology
Citation
Krekels, E.H.J, Neely, M.N, Panoilia, E, Tibboel, D, Capparelli, E.V, Danhof, M, … Knibbe, C.A.J. (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