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

Abstract

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.

Differences in P-glycoprotein activity in human and rodent blood–brain barrier assessed by mechanistic modelling

“…This means that accurate predictions in the CSF provide indirect information about the accuracy of the simulated drug concentrations in brain. In addition, the human brain model proved suitable for predicting brain parenchyma concentrations in previous studies, as was shown for morphine and AZD1775, but these compounds are less clear BBB Pgp substrates and therefore not used here (Li et al 2017 ; Verscheijden et al 2021 ). Predicted Kp ratios also correlated well with human clinical 11 C-verapamil PET values, as discussed above (Bauer et al 2015 ; Li et al 2017 ).…”

“…A 14 compartment PBPK model was developed in Rstudio version 3.6.2 based on a model published previously (Gaohua et al 2016 ; Verscheijden et al 2019 , 2021 ) (Fig. 1 ).…”

“…In addition, predictions for sub-groups such as children are possible by correcting for age-related differences in transporter expression (Verscheijden et al 2020a ). This has previously been used for predicting liver and kidney exposure, and recent studies proposed a similar approach for the brain (Kumar et al 2018 ; Li et al 2017 ; Neuhoff et al 2013a ; Verscheijden et al 2021 ).…”

In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition

“…Transporter kinetic obtained from such cell systems (mostly MDCK-MDR1, LLC-PK 1 -MDR1, MDCK-BCRP, and Caco-2), specifically when they are only driven by ATP-dependent transporter like MDR1 and BCRP, can be used, since the functionality of these transporters in the brain as matrix is unlikely different to the functionality in the in vitro cell system (as long as the driving force, i.e. ATP is supplied) ( 25 , 26 ). The passive permeability, however, may be different and the user should be aware of the assumptions made, when using these in vitro systems to estimate the passive permeability across the BBB.…”

Error traps in acute pain management in children

“…Similarly, neonates and premature infants do not metabolize or clear morphine at the same rate as adults or older children do 58 . Physiologically‐based pharmacokinetic and pharmacodynamic modeling also suggests that morphine's effects are largely underpredicted in neonates suggesting that age‐related differences in pharmacodynamics may play a role in the increased sensitivity to morphine observed around birth 59 . Hence, clinicians should consider alternative medications in those groups.…”