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.

Fig 1. Model verification of pharmacokinetic profiles in plasma and CSF of adults and children.

Panel (A): Adult morphine and M6G pharmacokinetic profiles and prediction errors (see methods, $\mathrm{P}\mathrm{E}=\frac{\mathrm{Y}\mathrm{o}\mathrm{b}\mathrm{s},\mathrm{i}-\mathrm{Y}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{d},\mathrm{m}\mathrm{e}\mathrm{d}\mathrm{i}\mathrm{a}\mathrm{n},\mathrm{i}}{(\mathrm{Y}\mathrm{o}\mathrm{b}\mathrm{s},\mathrm{i}+\mathrm{Y}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{d},\mathrm{m}\mathrm{e}\mathrm{d}\mathrm{i}\mathrm{a}\mathrm{n},\mathrm{i})/2}$) in plasma and CSF after single IV dose (0.38 mg/kg) morphine in neurosurgery patients. The black solid line indicates the median simulated value. The grey area represents 90% CI in inter-individual variability. Dotted lines indicate minimum and maximum simulated values. Dots are individual observed values from Meineke et al. (2002) [25]. Panel (B): Pediatric (1.4–15.9y) morphine and M6G pharmacokinetic profiles and prediction errors in plasma and CSF after single IV dose (0.25 mg/kg) morphine. The black solid line indicates the median simulated value. The grey area represents 90% CI in inter-individual variability. Dotted lines indicate minimum and maximum simulated values. Dots are observed values from Hain et al. (1999) [26].

Fig 2. Model verification of pharmacokinetic profiles in plasma, ECF and CSF of adults, children and neonates.

Panel (A): Morphine pharmacokinetic profiles in plasma and ECF after single IV infusion in adult (10 mg) and continuous IV infusion in pediatric (3.5–9.5 years, 30 μg/kg/h) traumatic brain injury patients. The black solid lines indicate median simulated values. The grey area represents 90% CI in inter-individual variability. Dotted lines indicate minimum and maximum simulated values. Dots are individual observed values from Bouw et al. (2001), Ederoth et al. (2003) and Ketharanathan et al. (2019) [–29]. Panel (B): Predicted and observed plasma morphine concentration in neonates after a IV dose of 0.1 mg/kg (upper panel: 1.1 days mean postnatal age, lower panel: 29 days mean postnatal age). The black solid lines indicated median simulated values. Dots are mean observed values from Pokela et al. (1993) [30]. Panel (C): Median predicted v.s. measured neonatal morphine CSF values after individualized (age, dose) simulations. Observed data was derived from Radboudumc CSF biobank. Panel (D): Morphine pharmacokinetic profiles in extracellular fluid after a single dose of 0.38 mg/kg IV morphine in adult individuals. Black line: Pgp not included. Red line: Pgp included.

Fig 3. Model verification of analgesic pharmacodynamic profiles in adults (pain tolerance) and children (pain score).

Panel (A): pain tolerance to an electrical pain stimulus (fraction of maximum tolerated current in milliampere) in adult healthy volunteers after (median) morphine doses from left to right of 0.13 mg/kg, 28 mg and 0.2 mg/kg IV, respectively. The black lines indicate median simulated values. The grey area represents 90% CI in inter-individual variability. Dotted lines indicate minimum and maximum simulated values. Dots represent observed values from Skarke et al. (2003), Dahan et al. (2004) and Sarton et al. (2000) [–33]. Vertical lines indicate mean +/- S.D. values (Sarton et al. and Skarke et al. [31,33]). Panel (B): Contribution to pharmacodynamic response by morphine or morphine-6-glucuronide (M6G) over time after 28 mg morphine IV. Panel (C): pharmacodynamic pain score profiles in children after IV morphine doses of 0.25 mg/kg (children 2.6–16.4 years) and 0.03 mg/kg (neonates 10–13 days), respectively. The black lines indicate median simulated values. The grey area represents 90% CI in inter-individual variability. Dotted lines indicate minimum and maximum simulated values. Dots are observed values from Mashayekhi et al. (2009) and Enders et al. (2008) [34,35]. Vertical lines indicate interquartile range (Enders et al. [35]).