A Multidose Study to Examine the Effect of Food on Evacetrapib Exposure at Steady State.
OBJECTIVE
To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants.


METHODS
This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for evacetrapib concentrations and pharmacokinetic parameter estimates including area under the concentration-time curve during a dosing interval (AUCτ), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated. Pharmacodynamic parameters, including cholesteryl ester transfer protein (CETP) activity, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, were also assessed.


RESULTS
A total of 34 males and 6 females, mean age 41.5 years and mean body mass index 26.6 kg/m(2), were enrolled. Statistical analysis showed AUCτ was 44% higher (90% confidence interval [CI]: 29%-62%) and Cmax was 51% higher (90% CI: 28%-79%) in the fed state than in the fasted state, indicating an effect of food. Consistent with higher evacetrapib exposure, changes in HDL-C, LDL-C, and CETP activity appeared to be greater in the fed state than in the fasted state. There were no notable changes in total cholesterol or triglycerides following administration in the fed and fasted states. The 130-mg doses of evacetrapib were well tolerated with and without food.


CONCLUSIONS
A high-fat meal increased evacetrapib mean exposure at steady state by 44% in healthy participants.
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA dsmall@lilly.com.
David S
DS
Small
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA.
Wei
W
Zhang
Covance Inc, Early Clinical Development, Evansville, IN, USA.
Jane
J
Royalty
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA.
Ellen A
EA
Cannady
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA.
Delyn
D
Downs
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA.
Stuart
S
Friedrich
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA.
Jeffrey G
JG
Suico
D000328:Adult; D000704:Analysis of Variance; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000097:blood / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D000924:Anticholesteremic Agents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D001569:Benzodiazepines; C568301:evacetrapib
cholesterol; cholesteryl ester transfer protein; evacetrapib; food effect