Title:
Evaluation of the use of static and dynamic models to predict drug-drug interaction and its associated variability: impact on drug discovery and early development.

Abstract:
Simcyp, a population-based simulator, is widely used for evaluating drug-drug interaction (DDI) risks in healthy and disease populations. We compare the prediction performance of Simcyp with that of mechanistic static models using different types of inhibitor concentrations, with the aim of understanding their strengths/weaknesses and recommending the optimal use of tools in drug discovery/early development. The inclusion of an additional term in static equations to consider the contribution of hepatic first pass to DDIs (AUCR(hfp)) has also been examined. A second objective was to assess Simcyp's estimation of variability associated with DDIs. The data set used for the analysis comprises 19 clinical interactions from 11 proprietary compounds. Except for gut interaction parameters, all other input data were identical for Simcyp and static models. Static equations using an unbound average steady-state systemic inhibitor concentration (I(sys)) and a fixed fraction of gut extraction and neglecting gut extraction in the case of induction interactions performed better than Simcyp (84% compared with 58% of the interactions predicted within 2-fold). Differences in the prediction outcomes between the static and dynamic models are attributable to differences in first-pass contribution to DDI. The inclusion of AUCR(hfp) in static equations leads to systematic overprediction of interaction, suggesting a limited role for hepatic first pass in determining inhibition-based DDIs for our data set. Our analysis supports the use of static models when elimination routes of the victim compound and the role of gut extraction for the victim and/or inhibitor in humans are not well defined. A fixed variability of 40% of predicted mean area under the concentration-time curve ratio is recommended.