CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome.

Aims: Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as 'add-on' therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug-drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated.

Methods: The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic.

Results: In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (K(i)) ranging from 0.57 µM (CYP2C9) to 7.6 µM (CYP2C19). Evacetrapib was a time-dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co-administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady-state, with no differences in reported hepatic or muscular adverse events.

Conclusions: Taken together, the extent of CYP-mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.