Top-Down Modeling Meets Bottom-Up Modeling: The Physiological and Physicochemical Basis for the Ontogeny of UGT2B7-Mediated Drug Glucuronidation.
E.H.J. Krekels (1,2), T.N. Johnson (3), S.M. den Hoedt (1), A. Rostami-Hodjegan (3,4), M. Danhof (1), D. Tibboel (2), C.A.J. Knibbe (1,2,5)
(1) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; (2) Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; (3) Simcyp Limited, Blades Enterprise Centre, Sheffield, UK; (4) School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK; (5) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Despite the multi-factorial nature of the ontogeny of drug clearance, paediatric population models often describe this process with a limited number of covariates in descriptive relationships. These covariate models quantify the influence of the sum of all underlying physiological changes for a given drug and preliminary proof-of-concept studies suggest that these covariate models can, in specific cases, be used for between drug extrapolations [1,2]. The current study examines the physiological and physicochemical basis of a paediatric covariate model for the ontogeny of UGT2B7-mediated glucuronidation in young children (top-down model) [1,3], by untangling the underlying maturational processes with a physiologically-based model (bottom-up model).
Methods: The physiologically-based modeling software Simcyp version 11 was used to simulate the glucuronidation clearance of morphine and zidovudine, both selective UGT2B7 substrates with intermediate hepatic extraction ratios, in 1000 children younger than 3 years. The main physiological and physicochemical drivers of the ontogeny profile of UGT2B7-mediated in vivo clearance were identified by changing system and drug parameters and evaluating the influence of these changes on the clearance ontogeny profile.
Results: Liver volume and UGT2B7 ontogeny influenced the ontogeny profile of in vivo morphine and zidovudine glucuronidation the most. Of the physicochemical drug parameters, logP and pKa both influenced the magnitude of glucuronidation clearance, but not the ontogeny pattern. A linear relationship was found between the unbound drug fraction, which is influenced by logP and pKa, and the magnitude of total clearance.
Conclusions: For drugs with intermediate extraction ratios liver volume and UGT2B7 ontogeny drive the ontogeny of in vivo glucuronidation. For drugs with similar extraction ratios, physicochemical drug properties do not influence the ontogeny profile, but only the magnitude of clearance, allowing for the extrapolation of paediatric population covariate models between these drugs. Situations involving extrapolation between drugs of varying extraction ratios and situations with non-linear drug metabolism need further investigation.
References:
[1] Krekels EHJ, Panoilia E, Neely M, Tibboel D, Capparelli E, Danhof M, Mirochnick M, Knibbe CAJ. Maturation of glucuronidation; a system specific property. PAGE 20 (2011) Abstr 2062
[2] De Cock RFW, Allegaert K, Sherwin CMT, De Hoog M, Van den Anker JN, Danhof M, Knibbe CAJ. Maturation of GFR in preterm and term neonates reflected by clearance of different antibiotics. PAGE 20 (2011) Abstr 2096
[3] Knibbe CA, Krekels EH, van den Anker JN, DeJongh J, Santen GW, van Dijk M, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin. Pharmacokinet. 2009;48(6):371-85.