Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children.

Autor: Verscheijden LFM; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands., Litjens CHC; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands., Koenderink JB; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Verbeek MM; Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands., de Wildt SN; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.; Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands., Russel FGM; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2021 Mar 04; Vol. 17 (3), pp. e1008786. Date of Electronic Publication: 2021 Mar 04 (Print Publication: 2021).
DOI: 10.1371/journal.pcbi.1008786
Abstrakt: Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day- 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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