Combining in vitro and in vivo pharmacokinetic data for prediction of hepatic drug clearance in humans by artificial neural networks and multivariatestatistical techniques

Several statistical regression models and artificial neural networks were u sed to predict the hepatic drug clearance in humans from in vitro (hepatocy te) and in vivo pharmacokinetic data and to identify the most predictive mo dels for this purpose. Cross-validation was performed to assess prediction accuracy. It turned out that human hepatocyte data was the best predictor, followed by rat hepatocyte data. Dog hepatocyte data and dog and rat in viv o data appear to be uncorrelated with human in vivo clearance and did not s ignificantly contribute to the prediction models. Considering the present, evaluation, the most cost-effective and most accurate approach to achieve s atisfactory predictions in human isa combination of in vitro clearances on human and rat hepatocytes. Such information is of considerable value to spe ed up drug discovery. This study also showed some of the limitations of the approach related to the size of the database used in the present evaluatio n.