Quantitative Prediction of Drug Interactions Caused by CYP1A2 Inhibitors and Inducers.

Abstract

A simple method to predict drug-drug interactions mediated by cytochrome P450 enzymes (CYPs) on the basis of invivo data has been previously applied for several CYP isoforms but not for CYP1A2. The objective of this study was to extend this method to drug interactions caused by CYP1A2 inhibitors and inducers. First, initial estimates of the model parameters were obtained using data from the literature. Then, an external validation of these initial estimates was performed by comparing model-based predicted area under the concentration-time curve (AUC) ratios with observations not used in the initial estimation. Third, refined estimates of the model parameters were obtained by Bayesian orthogonal regression using Winbugs software, and predicted AUC ratios were compared with all available observations. Finally, predicted AUC ratios for all possible substrates-inhibitors and substrates-inducers were computed. A total of 100 AUC ratios were retrieved from the literature. Model parameters were estimated for 19 CYP1A2 substrate drugs, 26 inhibitors and seven inducers, including tobacco smoking. In the external validation, the mean prediction error of the AUC ratios was -0.22, while the mean absolute error was 0.97 (37%). After the Bayesian estimation step, the mean prediction error was 0.11, while the mean absolute error was 0.43 (22%). The AUC ratios for 625 possible interactions were computed. This analysis provides insights into the interaction profiles of drugs poorly studied so far and can help to identify and manage significant interactions in clinical practice. Those results are now available to the community via a web tool ( http://www.ddi-predictor.org ).