Prediction of brain extracellular fluid concentrations: application to understanding central nervous system pharmacokinetics and pharmacodynamics Public Deposited

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  • March 21, 2019
  • Kalvass, John Cory
    • Affiliation: Eshelman School of Pharmacy
  • This project was pursued to evaluate the applicability of in vivo brain extracellular fluid concentrations, obtained via brain-homogenate equilibrium dialysis, to assess extent of CNS penetration and provide estimates of CNS biophase concentrations. Parallel experimentation was conducted to define the impact of blood-brain barrier (BBB) efflux on opioid pharmacokinetics/pharmacodynamics (PK/PD), and to evaluate mathematical approaches for assessing efflux transport kinetics. Steady-state unbound plasma-to-unbound brain concentration ratios and in vivo P-gp efflux ratios were determined in mice and used to evaluate extent of CNS distribution for 34 drugs. PK/PD studies were conducted with seven opioids to estimate ED50, serum EC50, and brain EC50; relevant in vitro and clinical parameters were used to construct in vitro-to-preclinical and preclinical-to-clinical comparisons of opioid potency. PK/PD studies were conducted in P-gp-deficient mice to assess the influence of BBB efflux transport on CNS PK/PD for opioid substrates of P-gp. Comprehensive mathematical modeling was employed to evaluate the influence of efflux, or efflux inhibition, on brain exposure, and to evaluate several potential metrics of efflux. The unbound plasma-to-unbound brain concentration ratio proved to be a valuable parameter for assessing the CNS distribution of drugs (equivalent to or superior to the in vivo P-gp efflux ratio). Opioid PK/PD studies indicated that, for centrally-active agents, unbound brain EC50,u was the best descriptor of in vivo intrinsic potency, resulting in a in vitro-to-in vivo correlation of r2~0.8. P-gp-mediated efflux attenuated central activity of fentanyl, methadone, and loperamide by decreasing brain-to-plasma ratios, but did not influence brain EC50. BBB efflux also decreased fentanyl, methadone, and loperamide brain:plasma equilibration half-life by ~2-fold, consistent with mathematical predictions. Mathematical modeling revealed that 50% inhibition of BBB efflux results in brain exposure increasing less than or equal to 2-fold; conventional mathematical treatment of efflux inhibition data overestimates Km and IC50. New mathematical relationships for expressing efflux activity and calculating Km and IC50 developed in this project overcomes limitations of conventional mathematical treatment. Knowledge of unbound brain concentrations and the influence of BBB efflux transport is important in developing a comprehensive understanding of CNS PK/PD for individual compounds or for members of a compound set.
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  • Pollack, Gary M.
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