Direct Comparison of the Prediction of the Unbound Brain-to-Plasma Partitioning Utilizing Machine Learning Approach and Mechanistic Neuropharmacokinetic Model

The mechanistic neuropharmacokinetic (neuroPK) model was established to predict unbound brain-to-plasma partitioning (K(p,uu,brain)) by considering in vitro efflux activities of multiple drug resistance 1 (MDR1) and breast cancer resistance protein (BCRP). Herein, we directly compare this model to a computational machine learning approach utilizing physicochemical descriptors and efflux ratios of MDR1 and BCRP-expressing cells for predicting K(p,uu,brain) in rats. Two different types of machine learning techniques, Gaussian processes (GP) and random forest regression (RF), were assessed by the time and cluster-split validation methods using 640 internal compounds. The predictivity of machine learning models based on only molecular descriptors in the time-split dataset performed worse than the cluster-split dataset, whereas the models incorporating MDR1 and BCRP efflux ratios showed similar predictivity between time and cluster-split datasets. The GP incorporating MDR1 and BCRP in the time-split dataset achieved the highest correlation (R(2) = 0.602). These results suggested that incorporation of MDR1 and BCRP in machine learning is beneficial for robust and accurate prediction. K(p,uu,brain) prediction utilizing the neuroPK model was significantly worse compared to machine learning approaches for the same dataset. We also investigated the predictivity of K(p,uu,brain) using an external independent test set of 34 marketed drugs. Compared to machine learning models, the neuroPK model showed better predictive performance with R(2) of 0.577. This work demonstrates that the machine learning model for K(p,uu,brain) achieves maximum predictive performance within the chemical applicability domain, whereas the neuroPK model is applicable more widely beyond the chemical space covered in the training dataset. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1208/s12248-021-00604-x.