CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs□S

Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candi-dates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in pre-clinical species. Measurement of enzyme inactivation rates (kinact and KI) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (kobs) at a single concentration of test compound (10 M). The advantages of this new assay format are highlighted by comparison with data generated using the IC50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically de-fined positive/negative kobs bin of 0.02 min 1, only 4 % of registered drugs were found to be positive. This proportion increased to more than 20 % when in-house lead optimization molecules were con-sidered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling