Integrating<i>invitro</i>ADMET data through generic physiologically based pharmacokinetic models

Early estimation of kinetics in man currently relies on extrapolation from experimental data generated in animals. Recent results from the application of a generic physiologically based model, Cloe PK) (Cyprotex), which is parameterised for human and rat physiology, to the estimation of plasma pharmacokinetics, are summarised in this paper. A comparison with predictive methods that involve scaling from in vivo animal data can also be made from recently published data. On average, the divergence of the predicted plasma concentrations from the observed data was 0.47 log units. For the external test set, > 70% of the predicted values of the AUC were within threefold of the observed values. Furthermore, the model was found to match or exceed the performance of three published interspecies scaling methods for estimating clearance, all of which showed a distinct bias towards overprediction. It is concluded that Cloe PK, as a means of integrating readily determined in vitro and/or in silico data, is a powerful, cost-effective tool for estimating exposure and kinetics in drug discovery and risk assessment that should, if widely adopted, lead to major reductions in the need for animal experimentation.