Modeling Pharmacokinetics in Steatotic Livers (SteaPKMod)

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*Challenge* Liver diseases lead to impairment of drug metabolism, making appropriate drug dosing difficult. Cellular metabolic capability and disease manifestation are subject to a spatially heterogeneous distribution at different physiologically relevant spatial scales: inhomogeneous across the entire organ, but also zonated within liver lobules, the smallest hepatic functional units. Drug metabolism can be expected to be most affected if diseased and metabolically active regions coincide.Current pharmacokinetics (PK) models take into account liver diseases in cumulative form, without representing the relevant spatial heterogeneity of disease-related local changes of metabolic capability. They hence lack indispensable capabilities for investigating the interplay between different patterns of heterogeneity and for predicting the specific impact of, e.g., zonated diseases or surgery on the overall metabolic capability.*Goal* We will develop a mathematical PK~model for individualized dosage optimization and diagnosis support in zonated and heterogeneously distributed liver diseases such as steatosis.This novel model will consider the interplay of spatially inhomogeneous metabolic capabilities and diseased states of cells and thus permit in silico investigations with unprecedented accuracy. Moreover, it will be the foundation for future clinical applications of decision support and risk assessment, e.g., by predicting remnant metabolic capacity after liver resections.*Approach* As showcases, we will investigate two example drugs representing classes of clinically relevant drugs metabolized by different cytochrome P450 enzymes (CYPs). PK~data will be obtained in normal mice and mice with alcoholic or non-alcoholic steatosis, two frequent and well-characterized liver diseases with distinct zonation patterns of lipid accumulations. Based on our feasibility study [DOI 10.1016/j.compbiomed.2016.04.004], we will quantify zonation and heterogeneity of steatotic lipid accumulations and the presence of enzymes.For the mathematical model using ordinary and partial differential equations, we will develop a novel mechanistic representation of how steatosis affects the hepatic cellular drug metabolism, e.g., via altered cellular properties, sinusoidal morphology, or hemodynamics at the relevant spatial scales. Tailored to the spatial multiscale structure of the model, we will implement drug-specific PK models. After successful validation of model predictions, we will apply the simulations for dosage optimization and for diagnosis support by deducing the underlying zonal alteration from changes in drug metabolism.With this preclinical proof of principle we will show that the approach is applicable for individualized therapy planning.