In vivo information-guided prediction approach for assessing the risks of drug-drug interactions associated with circulating inhibitory metabolites.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Zhe-Yi HuS Casey Laizure

Abstract

The in vivo drug-drug interaction (DDI) risks associated with cytochrome P450 inhibitors that have circulating inhibitory metabolites cannot be accurately predicted by conventional in vitro-based methods. A novel approach, in vivo information-guided prediction (IVIP), was recently introduced for CYP3A- and CYP2D6-mediated DDIs. This technique should be applicable to the prediction of DDIs involving other important cytochrome P450 metabolic pathways. Therefore, the aims of this study were to extend the IVIP approach to CYP2C9-mediated DDIs and evaluate the IVIP approach for predicting DDIs associated with inhibitory metabolites. The analysis was based on data from reported DDIs in the literature. The IVIP approach was modified and extended to CYP2C9-mediated DDIs. Thereafter, the IVIP approach was evaluated for predicting the DDI risks of various inhibitors with inhibitory metabolites. Although the data on CYP2C9-mediated DDIs were limited compared with those for CYP3A- and CYP2D6-mediated DDIs, the modified IVIP approach successfully predicted CYP2C9-mediated DDIs. For the external validation set, the prediction accuracy for area under the plasma concentration-time curve (AUC) ratios ranged from 70 to 125%. The accuracy (75-128...Continue Reading

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