Prediction of Compound Plasma Concentration–Time Profiles in Mice Using Random Forest

[Image: see text] Pharmacokinetic (PK) parameters such as clearance (CL) and volume of distribution (Vd) have been the subject of previous in silico predictive models. However, having information of the concentration over time profile explicitly can provide additional value like time above MIC or AUC, etc., to understand both the efficacy and safety-related aspects of a compound. In this work, we developed machine learning models for plasma concentration–time profiles after both i.v. and p.o. dosing for a series of 17 in-house projects. For explanatory variables, MACCS Keys chemical descriptors as well as in silico and experimental in vitro PK parameters were used. The predictive accuracy of random forest (RF), message passing neural network, 2-compartment models using estimated CL and Vdss, and an average model (as a control experiment) was investigated using 5-fold cross-validation (5-fold CV) and leave-one-project-out validation (LOPO-V). The predictive accuracy of RF in 5-fold CV for i.v. and p.o. plasma concentration–time profiles was the best among the models studied, with an RMSE for i.v. dosing at 0.08, 1, and 8 h of 0.245, 0.474, and 0.462, respectively, and an RMSE for p.o. dosing at 0.25, 1, and 8 h of 0.500, 0.612, and 0.509, respectively. Furthermore, by investigating the importance of the in vitro PK parameters using the Gini index, we observed that the general prior knowledge in ADME research was reflected well in the respective feature importance of in vitro parameters such as predicted human Vd (hVd) for the initial distribution, mouse intrinsic CL and unbound fraction of mouse plasma for the elimination process, and Caco2 permeability for the absorption process. Also, this model is the first model that can predict twin peaks in the concentration–time profile much better than a baseline compartment model. Because of its combination of sufficient accuracy and speed of prediction, we found the model to be fit-for-purpose for practical lead optimization.