Prediction of human pharmacokinetics from animal data and molecular structural parameters using multivariate...

The aim of the study reported here was to develop a regression equation for predicting oral clearance of various kinds of drugs in humans using experimental data from rats and dogs and molecular structural parameters. The data concerning the oral clearance of 87 drugs from rats, dogs, and humans were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, the molecular weight, calculated partition coefficient (c log P), and the number of hydrogen bond acceptors were used as possible descriptors related to oral clearance in human. Multivariate regression analyses, multiple linear regression analysis, and the partial least squares (PLS) method were used to predict oral clearance in human, and the predictive performances of these techniques were compared by allometric approaches, which have been used in interspecies scaling. Interaction terms were also introduced into the regression analysis to evaluate the nonlinear relationship. For the data set used in this study, the PLS model with the tertiary term descriptors gave the best predictive performance, and the value of the squared cross-validated correlation coefficient (q(2)) was 0.694. This PLS model, using animal oral clearance data for only two species and easily calculated molecular structural parameters, can generally predict oral clearance in human better than the allometric approaches. In addition, the molecular structural parameters and the interaction term descriptors were useful for predicting oral clearance in human by PLS. Another advantage of this PLS model is that it can be applied to drugs with various characteristics.