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PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th–95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5–2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

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Fig. 1
Fig. 2: The predicted (lines) and observed (points) plasma concentrations of morphine (blue) and M6G (yellow) following administration of morphine in human subjects.
Fig. 3: Predicted (lines) and observed (points) alterations of intracerebral exposure to morphine or M6G, and plasma exposure levels to M6G or naloxone.
Fig. 4: Sensitivity analysis and PD contributions analysis.
Fig. 5: Predicted (lines) and observed (points) alterations in miosis following intravenous or oral administration of morphine or M6G in human subjects.
Fig. 6: Predicted (lines) and observed (points) alterations in respiratory indexes following intravenous or oral administration of morphine or M6G in human subjects.
Fig. 7: Predicted (lines) and observed (points) alterations in analgesia following intravenous or oral administration of morphine or M6G in human subjects.
Fig. 8: Predicted and observed reversal effects of naloxone on CNS effects by iv or infusion of morphine or M6G.
Fig. 9: Simulation of morphine-induced respiratory depression risks and antagonistic effects of naloxone.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFC3300902).

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  1. Department of Pharmacology, College of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Rui-jing Mu, Tian-lei Liu, Xiao-dong Liu & Li Liu

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RJM and LL designed the research; RJM and XDL performed the research; RJM and TLL analyzed the data; RJM, and XDL wrote the manuscript.

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Correspondence to Xiao-dong Liu or Li Liu.

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Mu, Rj., Liu, Tl., Liu, Xd. et al. PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01255-2

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