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

Br J Clin Pharmacol. 2015 Dec;80(6):1388-98. doi: 10.1111/bcp.12730. Epub 2015 Oct 27.

Abstract

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.

Keywords: cholesteryl ester transfer protein; cytochrome P450; evacetrapib; organic anion transporter polypeptide; pharmacodynamic; pharmacokinetic.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / pharmacology*
  • Benzodiazepines / pharmacology*
  • Cells, Cultured
  • Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Double-Blind Method
  • Drug Interactions
  • Humans
  • Microsomes, Liver / enzymology
  • Midazolam / pharmacokinetics
  • Simvastatin / pharmacokinetics
  • Tolbutamide / pharmacokinetics

Substances

  • Anticholesteremic Agents
  • Cholesterol Ester Transfer Proteins
  • Cytochrome P-450 CYP3A Inhibitors
  • Benzodiazepines
  • evacetrapib
  • Tolbutamide
  • Simvastatin
  • Midazolam