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dc.contributor.authorCannady, E.-
dc.contributor.authorSuico, J.-
dc.contributor.authorWang, M.-
dc.contributor.authorFriedrich, S.-
dc.contributor.authorRehmel, J.-
dc.contributor.authorNicholls, S.-
dc.contributor.authorKrueger, K.-
dc.identifier.citationBritish Journal of Clinical Pharmacology, 2015; 80(6):1388-1398-
dc.description.abstractAIMS Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as ‘add-on’ therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug–drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated. METHODS The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic. RESULTS In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki) ranging from 0.57 μM (CYP2C9) to 7.6 μM (CYP2C19). Evacetrapib was a time-dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co-administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady-state, with no differences in reported hepatic or muscular adverse events. CONCLUSIONS Taken together, the extent of CYP-mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.-
dc.description.statementofresponsibilityEllen A. Cannady, Jeffrey G. Suico, Ming-Dauh Wang, Stuart Friedrich, Jessica R. F. Rehmel, Stephen J. Nicholls, Kathryn A. Krueger-
dc.rights© 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley 1388 / 1388–1398 / 80:6 / Br J Clin Pharmacol & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.-
dc.subjectcholesteryl ester transfer protein; cytochrome P450; evacetrapib; organic anion transporter polypeptide; pharmacodynamic; pharmacokinetic-
dc.titleCYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome-
dc.typeJournal article-
dc.identifier.orcidNicholls, S. [0000-0002-9668-4368]-
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