title: Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe.
abstract: OBJECTIVE
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland. michael.derks@roche.com
authors.forename: Michael
authors.initials: M
authors.lastname: Derks
authors.forename: Markus
authors.initials: M
authors.lastname: Abt
authors.forename: Mary
authors.initials: M
authors.lastname: Phelan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004952:Esters; D000069438:Ezetimibe; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D001384:Azetidines; D004952:Esters; D008055:Lipids; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D000069438:Ezetimibe