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Cannady EA, Wang MD, Friedrich S, et al. Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors. Pharmacol Res Perspect. 2015;3(5):e00179doi: 10.1002/prp2.179.
Cannady, E. A., Wang, M. D., Friedrich, S., Rehmel, J. L., Yi, P., Small, D. S., Zhang, W., & Suico, J. G. (2015). Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors. Pharmacology research & perspectives, 3(5), e00179. https://doi.org/10.1002/prp2.179
Cannady, Ellen A, et al. "Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors." Pharmacology research & perspectives vol. 3,5 (2015): e00179. doi: https://doi.org/10.1002/prp2.179
Cannady EA, Wang MD, Friedrich S, Rehmel JL, Yi P, Small DS, Zhang W, Suico JG. Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors. Pharmacol Res Perspect. 2015 Oct;3(5):e00179. doi: 10.1002/prp2.179. Epub 2015 Oct 12. PMID: 26516590; PMCID: PMC4618649.
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Pharmacol Res Perspect. 2015 Oct;3(5):e00179. doi: 10.1002/prp2.179. Epub 2015 Oct 12.

Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors.

Pharmacology research & perspectives

Ellen A Cannady, Ming-Dauh Wang, Stuart Friedrich, Jessica L F Rehmel, Ping Yi, David S Small, Wei Zhang, Jeffrey G Suico

Affiliations

  1. Departments of Clinical Pharmacology, Drug Disposition, Medical, and Statistics, Lilly Research Laboratories, Eli Lilly and Company Indianapolis, Indiana.

PMID: 26516590 PMCID: PMC4618649 DOI: 10.1002/prp2.179

Abstract

Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug-drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100-mg oral dose of (14)C-evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapib's CYP-associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and 2.30% of the dose was excreted in feces and urine, respectively. In clinical DDI studies, the ratios of geometric least squares means for evacetrapib with/without the CYP3A inhibitor ketoconazole were 2.37 for area under the curve (AUC)(0-∞) and 1.94 for C max. There was no significant difference in evacetrapib AUC(0-τ) or C max with/without the CYP2C8 inhibitor gemfibrozil, with ratios of 0.996 and 1.02, respectively. Although in vitro results indicated that both CYP3A and CYP2C8 metabolized evacetrapib, clinical studies confirmed that evacetrapib is primarily metabolized by CYP3A. However, given the modest increase in evacetrapib exposure and robust clinical safety profile to date, there is a low likelihood of clinically relevant DDI with concomitant use of strong CYP3A or CYP2C8 inhibitors.

Keywords: Cholesteryl ester transfer protein; cytochrome P450; evacetrapib; pharmacodynamic; pharmacokinetic

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