Abstract
Introduction In vitro measurements and predictions of human clinical pharmacokinetics (PK) are sometimes hindered and made impossible due to factors such as extensive binding to materials, low methodological sensitivity and large variability.
Methods The objective was to find compounds out of reach for in vitro PK-methods and (if possible) predict corresponding human clinical estimates using the ANDROMEDA by Prosilico software. In vitro methods selected for the investigation were human microsomes and hepatocytes for measuring and predicting intrinsic hepatic metabolic clearance (CLint), Caco-2 cells for measuring apparent intestinal permeability (Papp) for prediction of fraction absorbed (fa), plasma for measurement and estimation of unbound fraction (fu), and water and buffers for measuring solubility (S) for prediction of in vivo dissolution potential (fdiss).
Results and Conclusion 73 non-quantifiable in vitro PK-measurements for 70 compounds were found in the literature: 40 for CLint, 8 for Papp, 11 for fu and 14 for S. ANDROMEDA was successful in predicting all corresponding clinical PK-estimates for the selection of compounds with non-quantifiable in vitro PK, and predicted estimates were generally in line with observed in vivo data and results/problems at in vitro laboratories. Thus, ANDROMEDA is applicable for predicting human clinical PK for compounds out of reach for laboratory methods.
Competing Interest Statement
Urban Fagerholm, Ola Spjuth and Sven Hellberg declare shares in Prosilico AB, a Swedish company that develops solutions for human clinical ADME/PK predictions.
