Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP 3A and CYP 2C8 inhibitors

Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor ( CETP i) for reduction of risk of major adverse cardiovascular events in patients with high‐risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug–drug interactions ( DDI ) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 ( CYP ). The disposition, metabolism, and excretion of evacetrapib following a single 100‐mg oral dose of 14 C‐evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP 3A or CYP 2C8 inhibitors. In vitro, CYP 3A was responsible for about 90% of evacetrapib's CYP ‐associated clearance, while CYP 2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and 2.30% of the dose was excreted in feces and urine, respectively. In clinical DDI studies, the ratios of geometric least squares means for evacetrapib with/without the CYP 3A inhibitor ketoconazole were 2.37 for area under the curve ( AUC ) (0– ∞ ) and 1.94 for C max . There was no significant difference in evacetrapib AUC (0– τ ) or C max with/without the CYP 2C8 inhibitor gemfibrozil, with ratios of 0.996 and 1.02, respectively. Although in vitro results indicated that both CYP 3A and CYP 2C8 metabolized evacetrapib, clinical studies confirmed that evacetrapib is primarily metabolized by CYP 3A. However, given the modest increase in evacetrapib exposure and robust clinical safety profile to date, there is a low likelihood of clinically relevant DDI with concomitant use of strong CYP 3A or CYP 2C8 inhibitors.