title: Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model.
abstract: Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23-32weeks) received a loading dose of morphine (50-100μg/kg), followed by a continuous infusion (5-10μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Katrine Rørbæk
authors.initials: KR
authors.lastname: Knøsgaard
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmaceutical and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: David John Richard
authors.initials: DJ
authors.lastname: Foster
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Eva
authors.initials: E
authors.lastname: Sverrisdóttir
authors.affiliation: Australian Centre for Pharmacometrics and Sansom Institute, School of Pharmaceutical and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide, SA 5000, Australia. Electronic address: richard.upton@unisa.edu.au.
authors.forename: Richard Neil
authors.initials: RN
authors.lastname: Upton
authors.affiliation: Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA; Division of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Switzerland; Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: van den Anker
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010146:Pain / Q000097:blood / Q000188:drug therapy
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: Modelling; Morphine; Morphine-6-glucuronide; Pharmacokinetics/pharmacodynamics; Preterm neonates; Systematic model comparison