Wang C (1),(2), Sadhasivam S (3), Krekels EHJ (1),(2), Dahan A (4), Tibboel D (2), Danhof M (1), Knibbe CAJ (1),(2),(5)
(1) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (2) Erasmus MC Sophia Children’s Hospital, Intensive Care and Department of Paediatric Surgery, Rotterdam, The Netherlands, (3) Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA (4) Departments of Anesthesiology, Clinical Pharmacy and Toxicology, and Physiology, Leiden University Medical Center, Leiden, The Netherlands, (5) St. Antonius Hospital, Department of Clinical Pharmacy, Nieuwegein, The Netherlands
Objectives: Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential function [1]. Due to the high value for the exponent of this function, this model cannot be extrapolated to an older age-range. To scale clearance across the entire human life-span, recently, a bodyweight-dependent allometric exponent (BDE) model was developed on the basis of an allometric equation in which the exponent sigmoidally decreased with bodyweight [2]. The aim of current study is to extend the paediatric morphine model to a wider age-range using a BDE model.
Methods: Morphine and morphine-3-glucuronide (M3G) data from 356 (pre)term neonates, infants, children [3] and adults [4], and morphine data from 146 adolescents [unpublished study] were analyzed with NONMEM 7.2. Two scaling models were developed: I. in adults and children less than 3 years old taking into account morphine and M3G data; II. in all patients taking into account morphine data only. In model I, a previously published model [3] was used for morphine and M3G in which the BDE model [2] was tested as a covariate model for the formation and elimination clearance of M3G. In model II, a two-compartment model was used for morphine in which the BDE model [2] was tested as covariate model for total morphine clearance.
Results: In model I, the formation and elimination clearance of M3G was most adequately described by a BDE model in which the exponent was found to decrease from 1.44 to 0.83 for M3G formation and from 1 to 0.5 for M3G elimination. Half the decrease in exponents was reached at 4.2 and 5.4 kg, respectively. The stratified observed versus population predicted plots of M3G concentrations were unbiased for every age-group. In model II, similar descriptive and predictive performances were found as in model I. The exponent of the BDE model was found to decrease from 1.44 to 0.98 and half the decrease was reached at 4.2 kg.
Conclusions: The BDE model was able to scale both total morphine clearance and glucuronidation clearance through the M3G pathway across all age-ranges between (pre)term neonates and adults. The unbiased descriptive and predictive performance of the BDE models allow for further investigations in the ontogeny of UGT2B7-mediated drug glucuronidation.
References:
[1] Knibbe, C.A., et al., Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet, 2009. 48(6): p. 371-85.
[2] Wang, C., et al., A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span. Pharm Res, 2012.
[3] Krekels, E.H., et al., Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children. Clin Pharmacokinet, 2011. 50(1): p. 51-63.
[4] Sarton, E., et al., Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology, 2000. 93(5): p. 1245-54; discussion 6A.
Reference: PAGE 21 () Abstr 2523 [www.page-meeting.org/?abstract=2523]
Poster: Paediatrics