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

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 mu M for CYP2C8 to 82 + 4 mu M 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.