Table II.
Summary of pharmacokinetic and pharmacodynamic properties of Cholesterol Ester Transfer Protein (CETP) inhibitors
| Parameter | Torcetrapib | Dalcetrapib | Anacetrapib | Evacetrapib |
|---|---|---|---|---|
| Dose | 60 mg/day | 600 mg/day | 100 mg/day | 130 mg/day |
| Pharmacokinetics | ||||
| Bioavailability | 33 to 45% in rat and monkey | NA | 38% in rats, 13% in monkeys | NA |
| Effect of food on bioavailability | Exposure is higher in fed than fasted state | Exposure is higher (~65%) in fed versus fasted state | Exposure is 2–3 fold higher after low fat meal and 6–8 fold higher after high fat meal | NA |
| tmax (hour) | ~6 | ~3 | ~4 | NA |
| Main route of elimination | Hepatic metabolism | Hepatic metabolism | Hepatic metabolism | NA |
| Metabolism pathways | Oxidation (CYP3A4/5) and glucuronidation | Hydrolysis, glucuronidation, oxidation and methylation | Oxidation (CYP3A4 major) and glucuronidation | NA |
| Metabolites | To M2, then M1 and M4 | To dalcetrapib-thiol (active metabolite), then to dalcetrapib-S-Glu and dalcetrapib-S-methyl | To M1, then M2 and M3 | NA |
| Elimination half life (hour) | 373 total 211 unchanged |
25.5 ± 3.9 as dalcetrapib-thiol | 9 to 62 fasted 42–83 fed |
NA |
| Urine | 63% as conjugated metabolites | NA | < 2% | NA |
| Bile | 13% as metabolites | NA | Major route as oxidative metabolites | NA |
| Pharmacodynamics | ||||
| HDL-C | ↑ 72% | ↑ 31% | ↑ 138% | ↑ 129% |
| LDL-C | ↓ 25% | No change | ↓ 40% | ↓ 36% |
| Effect on CETP | Complete inhibition | Modulation | Complete inhibition | Complete inhibition |
| Heterotypic CE transfer | Inhibition | Inhibition | Inhibition | NA |
| Homotypic CE transfer | Inhibition | No effect | Inhibition | NA |
NA: not available, tmax: Time to maximum concentration, CE: Cholesteryl Ester, HDL-C:High-density lipoprotein cholesterol, LDL-C: Low-density lipoprotein cholesterol