In vitro and in vivo assessment of the effect of dalcetrapib on a panel of CYP substrates

Curr Med Res Opin. 2009 Apr;25(4):891-902. doi: 10.1185/03007990902790928.


Objective: The primary objective of this study was to investigate the drug-drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitro and clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone.

Research design and methods: Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC(50) for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug-drug interaction studies were conducted in healthy males: dalcetrapib 900 mg plus the Cooperstown 5 + 1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900 mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed.

Results: In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC(50) values ranged from 1.5 +/- 0.1 microM for CYP2C8 to 82 +/- 4 microM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900 mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900 mg on activity of CYP2C8. Dalcetrapib was generally well tolerated.

Conclusions: Although in vitro studies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900 mg dose, which is higher than the 600 mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amides
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cardiovascular Diseases / prevention & control*
  • Clinical Trials, Phase II as Topic
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Therapy, Combination
  • Enzyme Inhibitors / metabolism
  • Esters
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Male
  • Microsomes, Liver / enzymology*
  • Middle Aged
  • Rosiglitazone
  • Sulfhydryl Compounds / pharmacokinetics
  • Sulfhydryl Compounds / pharmacology*
  • Sulfhydryl Compounds / therapeutic use
  • Thiazolidinediones / metabolism
  • Young Adult


  • Amides
  • Enzyme Inhibitors
  • Esters
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Sulfhydryl Compounds
  • Thiazolidinediones
  • Rosiglitazone
  • dalcetrapib
  • Cytochrome P-450 Enzyme System
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • cytochrome P-450 CYP2D19 (marmoset)
  • CYP3A4 protein, human