Human Brain Penetration Prediction Using Scaling Approach from Animal Machine Learning Models

Machine learning (ML) approaches have been applied to predicting drug pharmacokinetic properties. Previously, we predicted rat unbound brain-to-plasma ratio (Kpuu,brain) by ML models. In this study, we aimed to predict human Kpuu,brain through animal ML models. First, we re-evaluated ML models for rat Kpuu,brain prediction by using trendy open-source packages. We then developed ML models for monkey Kpuu,brain prediction. Leave-one-out cross validation was utilized to rationally build models using a relatively small dataset. After establishing the monkey and rat ML models, human Kpuu,brain prediction was achieved by implementing the animal models considering appropriate scaling methods. Mechanistic NeuroPK models for the identical monkey and human dataset were treated as the criteria for comparison. Results showed that rat Kpuu,brain predictivity was successfully replicated. The optimal ML model for monkey Kpuu,brain prediction was superior to the NeuroPK model, where accuracy within 2-fold error was 78% (R² = 0.76). For human Kpuu,brain prediction, rat model using relative expression factor (REF), scaled transporter efflux ratios (ERs), and monkey model using in vitro ERs can provide comparable predictivity to the NeuroPK model, where accuracy within 2-fold error was 71% and 64% (R² = 0.30 and 0.52), respectively. We demonstrated that ML models can deliver promising Kpuu,brain prediction with several advantages: (1) predict reasonable animal Kpuu,brain; (2) prospectively predict human Kpuu,brain from animal models; and (3) can skip expensive monkey studies for human prediction by using the rat model. As a result, ML models can be a powerful tool for drug Kpuu,brain prediction in the discovery stage.