(470e) CFD-Based Validation of Drug Metabolism from Clinical Data in 3D Configuration | AIChE

(470e) CFD-Based Validation of Drug Metabolism from Clinical Data in 3D Configuration

Authors 

German, C. - Presenter, Oklahoma State University
Madihally, S., Oklahoma State University
Successful evaluation of efficiency and safety of new medicines is a time consuming and expensive process. The incorporation of in silico methods in preclinical stages of drug development has increased significantly over the recent years as a result of low cost and high capacity data producing abilities. Additionally, recent trends suggest a sway toward a “learn and confirm” process, rather than the traditional multi-phased progression, that could lead to increased success. However, there is currently no systematic validation approach that bridges the gap between experimental data, computational simulation, and patient results by examining metabolic profiles. With the extensive amount of experimental data available, it is vital to find a way to connect small-scale, experimental data to large-scale, clinical data. In this regard, we evaluated the metabolism of the popular drug, acetaminophen (APAP), using kinetic data from literature in a computational simulation. We evaluated the metabolism of APAP to produce three major metabolites well studied in literature. First we converted available pharmacokinetic data on sulfation, glucourinidation and CYP pathway based on CYP 3A4/5, 2D6, 2A6, 2E1 and 1A2 isoforms to per cell basis and to the whole liver. Then simulations were performed using commercially available computational fluid dynamics (CFD) software (Comsol Multiphysics 5.2a) in a smaller 3D porous space that could be cultured in standard 24-well and 96-well plates. We considered contributions from CYP isoforms in four different configurations: i) individual, ii) accounting for activity, iii) accounting for abundance, and iv) grouped average. Using the results we compare the output to clinical data. We also tested the effect of dosage and cell number that are typically varied in cell culture to the output metabolic profiles. These evaluations show that one could test the values of pharmacokinetic data, CYP isoform information, and compare to clinical data. Activity-based isoform analysis largely agrees with clinical data. Also, upon validation these profiles can be utilized in the development of synthetic liver constructs.