The increasing prevalence of artificial agents creates a correspondingly increasing need to manage disagreements between humans and artificial agents, as well as between artificial agents themselves. Considering this larger space of possible agents exposes an opportunity for furthering our understanding of the nature of disagreement: past studies in psychology have often cast disagreement as two agents forming diverging evaluations of the same object, but disagreement can also arise from differences in how agents represent that object. AI research on human-machine alignment and recent work in computational cognitive science have focused on this latter kind of disagreement, and have developed tools that can be used to quantify the extent of representational overlap between agents. Understanding how divergence and misalignment interact to produce disagreement, and how resolution strategies depend on this interaction, is key to promoting effective collaboration between diverse types of agents.

A 4-compartment permeability-limited brain (4Brain) model consisting of brain blood, brain mass, cranial and spinal cerebrospinal fluid (CSF) compartments has been developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator. The model assumptions, structure, governing equations and system parameters are described. The model in particular considers the anatomy and physiology of the brain and CSF, including CSF secretion, circulation and absorption, as well as the function of various efflux and uptake transporters existing on the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), together with the known parameter variability. The model performance was verified using in vitro data and clinical observations for paracetamol and phenytoin. The simulated paracetamol spinal CSF concentration is comparable with clinical lumbar CSF data for both intravenous and oral doses.

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