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Drug-Drug-Interaction Working Groups

The FDA/IQ/Academia Prediction of Drug-Drug Interaction Inhibition/Inactivation and Induction Working Groups seek to assess the performance of various method(s) that use in vitro data to provide quantitative forecasts of clinical DDI across a broad range of drugs. The findings will be used to justify which of the approaches offer meaningful input to clinical DDI study strategies.

The first activity of the Working Groups was to identify the models and approaches currently available for predicting DDI. The approaches ranged from correlation-type methods and basic “static” algorithms to more complex “dynamic” physiologically-based pharmacokinetic (PBPK) models. Secondly, the Working Groups made recommendations to standardize important input parameters, particularly for common CYP3A victim drugs (e.g. fmCYP, FG), to use in the models. The DDI trials that were chosen as models were identified from literature references or from internal company sources that focused on midazolam as a victim drug (for inhibition/inactivation) and inclusion of more CYP3A substrates (e.g. alprazolam, simvastatin, nifedipine) for CYP3A induction predictions. The predictability of the correlation or “static” models was assessed using various surrogates for the perpetrator concentration. The dynamic perpetrator concentration in the PBPK model was qualified with known clinical PK data.

The results of the prediction assessment and final recommendations from these Working Groups will be presented within two research papers.