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- W4328134606 abstract "Abstract Morphine blood-brain barrier (BBB) transport is governed by passive diffusion, active efflux and saturable active influx. These processes may be associated with nonlinear concentration-dependencies which impact plasma and brain extracellular fluid (brain ECF ) pharmacokinetics of morphine. In this study, we aim to evaluate the impact of nonlinear BBB transport on brain ECF pharmacokinetics of morphine and its metabolites for different dosing strategies using a physiologically based pharmacokinetic simulation study. We extended the human physiologically based pharmacokinetic, LeiCNS-PK3.0, model with equations for nonlinear BBB transport of morphine. Simulations for brain ECF pharmacokinetics were performed for various dosing strategies: intravenous (IV), oral immediate (IR) and extended release (ER) with dose range of 0.25-150mg and dosing frequencies of 1-6 times daily. The impact of nonlinear BBB transport on morphine CNS pharmacokinetics was evaluated by quantifying (i) the relative brain ECF to plasma exposure (AUC u,brainECF /AUC u,Plasma ) and (ii) the impact on the peak-to-trough ratio (PTR) of concentration-time profiles in brain ECF and plasma. We found that the relative morphine exposure and PTRs are dose dependent for the evaluated dose range. The highest relative morphine exposure value of 1.4 was found for once daily 0.25mg ER and lowest of 0.1 for 6-daily 150mg IV dosing. At lower doses the PTRs were smaller and increased with increasing dose and stabilized at higher doses independent of dosing frequency. Relative peak concentrations of morphine in relation to its metabolites changed with increasing dose. We conclude that nonlinearity of morphine BBB transport affect the relative brain ECF exposure and the fluctuation of morphine and its metabolites. Highlights Nonlinear transport affects relative morphine exposure in brain ECF . Nonlinear transport affects PK fluctuations of morphine in brain ECF . Nonlinear transport affects brain ECF PK relationship of morphine and its metabolites. Graphical abstract" @default.
- W4328134606 created "2023-03-22" @default.
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- W4328134606 date "2023-03-21" @default.
- W4328134606 modified "2023-09-26" @default.
- W4328134606 title "Does nonlinear blood-brain barrier transport matter for morphine dosing strategies?" @default.
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- W4328134606 doi "https://doi.org/10.1101/2023.03.17.533135" @default.
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