Optimizing Higher Throughput Methods to Assess Drug-Drug Interactions for CYP1A2, CYP2C9, CYP2C19, CYP2D6, rCYP2D6, and CYP3A4 In Vitro Using a Single Point IC50

Drug-drug interactions involving cytochrome P450 (CYP) are an important factor in whether a new chemical entity will survive through to the development stage. Therefore, the identification of this potential as early as possible in vitro could save considerable future unnecessary investment. In vitro CYP interaction screening data generated for CYP2C9, CYP2D6, and CYP3A4 were initially analyzed to determine the correlation of IC50 from 10- and 3-point determinations. A high correlation (r = 0.99) prompted the further assessment of predicting the IC50 by a single value of percent inhibition at either 10, 3, or 1 AM. Statistical analysis of the initial proprietary compounds showed that there was a strong linear relationship between log IC50 and percent inhibition at 3,M, and that it was possible to predict a compound's IC50 by the percent inhibition value obtained at 3 AM. Additional data for CYP1A2, CYP2C19, and the recombinant CYP2D6 were later obtained and used together with the initial data to demonstrat...