Article date: December 2010
By: Michael Derks, Markus Abt, Mary Phelan, in Volume 70, Issue 6, pages 825-833
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
AIMS
Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid‐modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints.
METHODS
Co‐administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment.
RESULTS
Co‐administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for Cmax. Ezetimibe exposure was reduced with co‐administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for Cmax for total ezetimibe. High‐density lipoprotein cholesterol increases associated with co‐administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low‐density lipoprotein cholesterol with co‐administration (−35.9%) was greater than with ezetimibe alone (−20.9%). Dalcetrapib was generally well tolerated when administered alone and when co‐administered with ezetimibe.
CONCLUSION
Co‐administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug.
DOI: 10.1111/j.1365-2125.2010.03763.x
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