Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 1

An In Vitro - In Vivo Correlation Method for CYP Induction

Kenneth R. Korzekwa, Ph.D.
AllChemie Inc.

A set of 76 diverse compounds for which there is clinical drug-drug interaction data were used to develop an in vitro-in vivo correlation method for induction. The dataset included 38 inducers and 38 non-inducers. Induction in hepatocytes was determined by CYP3A4 message and activity. PXR activity was also measured in a transactivation assay. Fractions unbound in plasma and hepatocytes were used to correct in vitro and in vivo concentrations. Clinical data from 240 studies were used with the in vitro data to develop a model for P450 induction. Including both pre-systemic and systemic induction resulted in a model that can correctly identify >90% of the clinically significant inducers and non-inducers in the dataset.

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