Direct Comparison of Total Clearance Prediction: Computational Machine Learning Model versus Bottom-Up Approach Using In Vitro Assay

Abstract

The in vitro-in vivo extrapolation (IVIVE) approach for predicting total plasma clearance (CLtot) has been widely used to rank order compounds early in discovery. More recently, a computational machine learning approach utilizing physicochemical descriptors and fingerprints calculated from chemical structure information has emerged, enabling virtual predictions even earlier in discovery. Previously, this approach focused more on in vitro intrinsic clearance (CLint) prediction. Herein, we directly compare these two approaches for predicting CLtot in rats. A structurally diverse set of 1114 compounds with known in vivo CLtot, in vitro CLint, and plasma protein binding was used as the basis for this evaluation. The machine learning models were assessed by validation approaches using the time- and cluster-split training and test sets, and five-fold cross validation. Assessed by five-fold validation, the random forest regression (RF) and radial basis function (RBF) models demonstrated better prediction performance in eight attempted machine learning models. The CLtot values predicted by the RF and RBF models were within two-fold of the observed values for 67.7 and 71.9% of cluster-split test set compounds, respectively, while the predictivity was worse in the time-split dataset. The predictivity of both models tended to be improved by incorporating in vitro parameters, unbound fraction in plasma (fu,p), and CLint. CLtot prediction utilizing in vitro CLint and the well-stirred model, correcting for the fraction unbound in blood, was substantially worse compared to machine learning approaches for the same cluster-split test set. The reason that CLtot is underestimated by IVIVE is not fully explained by considering the calculated microsomal unbound fraction (cfu,mic), extended clearance classification system (ECCS), and omitting high clearance compounds in excess of hepatic blood flow. The analysis suggests that in silico machine learning models may have the power to reduce reliance on or replace in vitro and in vivo studies for chemical structure optimization in early drug discovery.