Development AND External validation of a model for Glucuronidation in children below 3 years of age using morphine as a model drug; towards a novel dosing paradigm.
Elke H.J. Krekels1,2, Gijs W.E. Santen1, John N. van den Anker2,3, Joost de Jongh1,4, Evelyne M. Jacqz-Aigrain5, Caroline D. van der Marel2,6, Richard A. van Lingen7, Anne M. Lynn8, Monique van Dijk2, Sinno Simons2, Meindert Danhof1, Dick Tibboel2, Catherijne A.J. Knibbe1,2,9
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. Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA; 4. LAP&P consultants, Leiden, The Netherlands; 5. Department of Pediatric Pharmacology and Pharmacogenetics, Hopital Robert Debre, Paris, France; 6. Department of Anesthesiology, Erasmus MC, Rotterdam, The Netherlands; 7. Princess Amalia Department of Pediatrics, Division of Neonatology, Isala Clinics, Zwolle, The Netherlands; 8. University of Washington School of Medicine, Childrens’s Hospital and Regional Medical Center, Seattle, WA, USA 9. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: In pediatrics, drugs are often dosed in mg/kg, regularly requiring higher or lower dosages per kg with increasing age. To derive rational dosing schemes we developed a population PK model that described the influence of age on glucuronidation capacity by the UGT2B7 enzyme in newborns, including preterms, and infants younger than 3 years using morphine and its two major metabolites as a model drug. The model was validated both internally and externally.
Methods: Based on a meta-analysis of sparse data, a population pharmacokinetic model was developed using NONMEM. The data included 2159 concentrations of morphine and its glucuronides from 248 infants weighing 500 g to 18 kg receiving intravenous morphine as a bolus dose or continuous infusion [1,2]. Using the NPDE method as proposed by Brendel et al.  the model was validated both internally and externally to various datasets.
Results: Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were adequately described using an allometric equation based on bodyweight, with an estimated exponential scaling factor of approximately 1.5. A postnatal age of less than 10 days was identified as an additional covariate for formation clearance to the glucuronides. Distribution volumes scaled linearly with bodyweight. The internal and external validation procedure demonstrated that morphine and its metabolite concentrations in the individual patient can be predicted based on dosing regimen, postnatal age and bodyweight alone, thereby proving that the model can be used for simulations and the development of new dosing regimens.
Conclusions: The validated model shows that a loading dose in μg/kg and a maintenance dose expressed in μg/kg1.5/ h-1, with a 50% maintenance dose reduction in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age-range. Once the target concentrations across this age-range have been determined, this model can be used to establish final dosing recommendations. Additionally, future cross-validation studies have to reveal whether the results from this study can be extrapolated to other drugs metabolized by the same enzyme.
 Van Dijk et al. PAIN 98(3); 305-313 (2002)
 Simons et al. JAMA 298(18); 2419-2427 (2003)
 Brendel et al. Pharm. Res. 23(9); 2036-2049 (2006)