Maturation of glucuronidation; a system specific property
Elke H.J. Krekels(1,2), Eirini Panoilia(3), Michael Neely(4), Dick Tibboel(2), Edmund Capparelli(5), Meindert Danhof(1), Mark Mirochnick(6), Catherijne A.J. Knibbe(1,7)
(1) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; (2) Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; (3) Laboratory of Pharmacokinetics, University of Patras, Patras, Greece; (4) LAC / USC Medical Center, University of Southern California, Los Angeles, CA USA; (5) Department of Pediatrics UC San Diego, La Jolla, CA USA (6) Division of Neonatology, Boston University, Boston, MA USA; (7) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: The maturation of morphine and propofol glucuronidation in children younger than 3 years was found to be best described by a bodyweight-based exponential equation with a similar exponents of 1.44 and 1.45 respectively1,2. This function is hypothesized to be a ‘system specific' rather than a ‘drug specific' property, which would imply that it can be extrapolated to other drugs that are metabolized through glucuronidation. This hypothesis is tested in the current study.
Methods: The current analysis was based on a dataset containing 473 zidovudine concentrations and 173 zidovudine-glucuronide concentrations collected in 29 individuals varying from term neonates to infants up to 5 months of age3. Two models were fit to these data, the first model used the developmental glucuronidation covariate model obtained previously with morphine. In this model, maturation of glucuronidation was described by bodyweight in an exponential equation with an exponent of 1.44 with reduced clearance capacity in neonates younger than 10 days. For the second model a comprehensive covariate model was developed using a systematic covariate analysis, this provides the best possible description of the data and therefore the comprehensive covariate model served as a reference model. In the comprehensive covariate model the most predictive covariate for glucuronidation maturation in the current dataset was postnatal age in a sigmoidal equation.
Results: Despite the different determinants for maturation of glucuronidation clearance between the two models, the developmental glucuronidation model obtained with morphine had similar descriptive and predictive properties compared to the fully optimized reference model, based on basic goodness-of-fit plots and NPDE analysis. The difference in the obtained covariate relationships are probably the result of the high correlation between bodyweight and age and the differences in age-range in the datasets on which the covariate models are based.
Conclusions: These findings support our hypothesis that maturation of drug metabolism is a system specific property. Provided a model is based on a sufficient number of individuals, broad range in covariate values and fully validated, use of information on maturational processes obtained in one drug, can significantly reduce time and costs of paediatric model development for new drugs.
References:
[1] Knibbe et al. Clin Pharmacokinet. (2009); 48(6):371-385
[2] Wang et al. PAGE 19 (2010); abstract 1818
[3] Boucher et al. J.Pediatr. (1993); 122(1):137-144
