CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: In vitro prediction and clinical outcome

Ellen A. Cannady, Jeffrey G. Suico, Ming Dauh Wang, Stuart Friedrich, Jessica R.F. Rehmel, Stephen J. Nicholls, Kathryn A. Krueger

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 (K i ) 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.

LanguageEnglish
Pages1388-1398
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume80
Issue number6
DOIs
Publication statusPublished - 1 Dec 2015

Keywords

  • cholesteryl ester transfer protein
  • cytochrome P450
  • evacetrapib
  • organic anion transporter polypeptide
  • pharmacodynamic
  • pharmacokinetic

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Cannady, E. A., Suico, J. G., Wang, M. D., Friedrich, S., Rehmel, J. R. F., Nicholls, S. J., & Krueger, K. A. (2015). CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: In vitro prediction and clinical outcome. British Journal of Clinical Pharmacology, 80(6), 1388-1398. https://doi.org/10.1111/bcp.12730
Cannady, Ellen A. ; Suico, Jeffrey G. ; Wang, Ming Dauh ; Friedrich, Stuart ; Rehmel, Jessica R.F. ; Nicholls, Stephen J. ; Krueger, Kathryn A. / CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor : In vitro prediction and clinical outcome. In: British Journal of Clinical Pharmacology. 2015 ; Vol. 80, No. 6. pp. 1388-1398.
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abstract = "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 (K i ) 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.",
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CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor : In vitro prediction and clinical outcome. / Cannady, Ellen A.; Suico, Jeffrey G.; Wang, Ming Dauh; Friedrich, Stuart; Rehmel, Jessica R.F.; Nicholls, Stephen J.; Krueger, Kathryn A.

In: British Journal of Clinical Pharmacology, Vol. 80, No. 6, 01.12.2015, p. 1388-1398.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor

T2 - British Journal of Clinical Pharmacology

AU - Cannady, Ellen A.

AU - Suico, Jeffrey G.

AU - Wang, Ming Dauh

AU - Friedrich, Stuart

AU - Rehmel, Jessica R.F.

AU - Nicholls, Stephen J.

AU - Krueger, Kathryn A.

PY - 2015/12/1

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N2 - 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 (K i ) 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.

AB - 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 (K i ) 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.

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KW - cytochrome P450

KW - evacetrapib

KW - organic anion transporter polypeptide

KW - pharmacodynamic

KW - pharmacokinetic

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