Lack of clinically relevant drug–drug interactions when dalcetrapib is co-administered with ezetimibe

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? Dalcetrapib, which targets cholesteryl ester transfer protein, is currently in phase III development to evaluate its effect on the prevention of cardiovascular events. It will likely be co-administered with other lipid-modifying drugs such as the cholesterol absorption inhibitor ezetimibe. There are currently no studies on the co-administration of dalcetrapib with ezetimibe.WHAT THIS STUDY ADDS? This study showed no clinically relevant pharmacokinetic interactions when dalcetrapib was co-administered with ezetimibe. The effect of dalcetrapib on raising high-density lipoprotein cholesterol was not compromised, and there was an additive effect on low-density lipoprotein cholesterol lowering with co-administration of dalcetrapib with ezetimibe compared with ezetimibe alone. Dalcetrapib alone or co-administered with ezetimibe was not associated with an increased rate of adverse events compared with ezetimibe alone.AIMSDalcetrapib, 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.METHODSCo-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.RESULTSCo-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 C_max. 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 C_max 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.CONCLUSIONCo-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.