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

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