In this study, we investigated practical in silico methods for predicting compound brain concentration-time profiles in mice. First, we built a hybrid model linking the plasma concentration-time profile to the brain compartment using observed brain concentration-time data with high reproducibility. Second, using the parameters fitted in the hybrid model, we applied the predicted parameters using RF models to the hybrid model and obtained moderate accuracy. Third, using initial inputs of parameters predicted by the RF models and brain concentrations at 1 h, we estimated the brain concentration at other time points with high accuracies.