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

• Published in: British journal of clinical pharmacology 2015-12, Vol.80 (6), p.1388-1398
• Main Authors: Cannady, Ellen A., Suico, Jeffrey G., Wang, Ming‐Dauh, Friedrich, Stuart, Rehmel, Jessica R. F., Nicholls, Stephen J., Krueger, Kathryn A.
• Format: Article
• Language: English
• Subjects: Anticholesteremic Agents - pharmacology; Benzodiazepines - pharmacology; Cells, Cultured; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; cholesteryl ester transfer protein; Cytochrome P-450 CYP3A Inhibitors - pharmacology; cytochrome P450; Double-Blind Method; Drug Interactions; evacetrapib; Humans; Microsomes, Liver - enzymology; Midazolam - pharmacokinetics; organic anion transporter polypeptide; pharmacodynamic; pharmacokinetic; Simvastatin - pharmacokinetics; Tolbutamide - pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12730

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 (Ki) 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.