Physiologically Based Pharmacokinetic/Pharmacodynamic Model For The Prediction Of Morphine Brain Disposition And Analgesia In Adults And Children

Author summaryDevelopmental processes in children can affect pharmacokinetics: "what the body does to the drug" as well as pharmacodynamics: "what the drug does to the body". A typical example is morphine, of which the analgesic response is variable and particularly neonates suffer more often from respiratory depression, even when receiving doses corrected for differences in elimination. One way to mathematically incorporate developmental processes is by employing physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) models, where physiological differences between individuals are incorporated. In this study, we developed a morphine PB-PK/PD model to predict brain drug disposition as well as analgesic response in adults and children, as both processes could potentially contribute to developmental variability in the effect of morphine. We found that age-related variation in BBB expression of the main morphine efflux transporter P-glycoprotein was not responsible for differences in brain exposure. In contrast, pharmacodynamic modelling suggested an increased sensitivity to morphine in neonates.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.