CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome.
OBJECTIVE
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.
Eli Lilly and Company, Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Ellen A
EA
Cannady
Eli Lilly and Company, Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.|Principal Investigator, Eli Lilly and Company, Indianapolis, Indiana, USA.
Jeffrey G
JG
Suico
Eli Lilly and Company, Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Ming-Dauh
MD
Wang
Eli Lilly and Company, Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Stuart
S
Friedrich
Eli Lilly and Company, Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Jessica R F
JR
Rehmel
South Australian Health & Medical Research Institute, University of Adelaide, Adelaide, Australia.|Principal Investigator, Eli Lilly and Company, Indianapolis, Indiana, USA.
Stephen J
SJ
Nicholls
Eli Lilly and Company, Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Kathryn A
KA
Krueger
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D008874:Midazolam / Q000493:pharmacokinetics; D019821:Simvastatin / Q000493:pharmacokinetics; D014044:Tolbutamide / Q000493:pharmacokinetics
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D065692:Cytochrome P-450 CYP3A Inhibitors; D001569:Benzodiazepines; C568301:evacetrapib; D014044:Tolbutamide; D019821:Simvastatin; D008874:Midazolam
cholesteryl ester transfer protein; cytochrome P450; evacetrapib; organic anion transporter polypeptide; pharmacodynamic; pharmacokinetic