CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome
Autor: | Ming Dauh Wang, Stephen J. Nicholls, Ellen A. Cannady, Stuart Friedrich, Jessica Rehmel, Jeffrey G. Suico, Kathryn A. Krueger |
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Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Simvastatin
cytochrome P450 Midazolam Tolbutamide cholesteryl ester transfer protein evacetrapib CYP2C19 Pharmacology chemistry.chemical_compound Benzodiazepines Pharmacokinetics Double-Blind Method Cholesterylester transfer protein medicine organic anion transporter polypeptide Humans Pharmacology (medical) Drug Interactions pharmacokinetic CYP2C9 CETP inhibitor Cells Cultured biology Chemistry Anticholesteremic Agents Cholesterol Ester Transfer Proteins pharmacodynamic Pharmacodynamics biology.protein Microsomes Liver Cytochrome P-450 CYP3A Inhibitors Evacetrapib medicine.drug |
Zdroj: | British Journal of Clinical Pharmacology |
ISSN: | 1365-2125 0306-5251 |
Popis: | Aims 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. |
Databáze: | OpenAIRE |
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