Effect of Diltiazem, a Moderate CYP3A Inhibitor, on the Pharmacokinetics of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein Inhibitor, in Healthy Subjects

Garg, Amit; Maes, Andrea; Corr, Christy; Jin, Bo; Wadhwa, Tarun; Handa, Nikhil; Dyck, Kristien Van; Lepeleire, Inge De; Shah, Jinesh; Wagner, John A.; Krishna, Rajesh

doi:10.1177/0091270010368676

Cited by 14 publications

(11 citation statements)

References 13 publications

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“…Given that ketoconazole is a commonly used probe and a potent CYP3A4 inhibitor, moderate and weak CYP3A4 inhibitors are expected to have comparatively less meaningful effects on anacetrapib pharmacokinetics. This is confirmed by the results of a drug interaction study in which diltiazem increased anacetrapib exposures to a lesser extent than ketoconazole 83 . A midazolam probe study in healthy subjects indicated that anacetrapib neither inhibits nor induces CYP3A4 activity 77 .…”

Section: Anacetrapib Pharmacokineticsmentioning

confidence: 65%

“…This is confirmed by the results of a drug interaction study in which diltiazem increased anacetrapib exposures to a lesser extent than ketoconazole. 83 A midazolam probe study in healthy subjects indicated that anacetrapib neither inhibits nor induces CYP3A4 activity. 77 There is no clinically meaningful pharmacokinetic interaction between anacetrapib and simvastatin.…”

Section: Anacetrapib Pharmacokineticsmentioning

confidence: 99%

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Anacetrapib, a Novel CETP Inhibitor: Pursuing a New Approach to Cardiovascular Risk Reduction

Gutstein

Krishna

Johns

et al. 2011

Clin Pharmacol Ther

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Cholesteryl ester transfer protein (CETP) inhibition is a promising experimental strategy to raise high-density lipoprotein cholesterol (HDL-C) and reduce cardiovascular risk. This review focuses on the highly selective and potent CE TP inhibitor anacetrapib and discusses the available preclinical and clinical information pertaining to it. We also describe strategies to target HDL-C, discuss the mechanism underlying CETP inhibition and its effects on lipid biology, and give an overview of other CETP inhibitors that are currently in development.

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Section: Anacetrapib Pharmacokineticsmentioning

confidence: 65%

Section: Anacetrapib Pharmacokineticsmentioning

confidence: 99%

Anacetrapib, a Novel CETP Inhibitor: Pursuing a New Approach to Cardiovascular Risk Reduction

Gutstein

Krishna

Johns

et al. 2011

Clin Pharmacol Ther

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“…Other studies showed that anacetrapib did not significantly interact with other drugs. Anacetrapib was not a potent inhibitor or inducer of the cytochrome P450 family of enzymes [46][47][48]. It did not affect the pharmacokinetics of simvastatin [47].…”

Section: Efficacymentioning

confidence: 85%

CETP Inhibitors: Will They Live up to Their Promise?

Cheung

Hegele

2011

Curr Cardiovasc Risk Rep

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Cholesterol ester transfer protein (CETP) exchanges lipids between circulating plasma lipoproteins and has been considered as an excellent drug target for raising plasma levels of high-density lipoprotein (HDL) cholesterol. However, HDL displays considerably more complexity than low-density lipoprotein (LDL) in terms of structure, proteomics, and several physiologic functions. After the discouraging results from clinical trials of torcetrapib (an early inhibitor of CETP that dramatically raised HDL cholesterol levels), there is renewed hope that dalcetrapib and anacetrapib are sufficiently different structurally and functionally to justify large-scale clinical end point studies. In fact, such trials are already underway in the case of dalcetrapib and are imminent in the case of anacetrapib. These end point trials will show whether CETP inhibition will live up to its promise for atheroprotection.

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“…Ezetimibe and statins lower LDL‐C by different mechanisms, and co‐administration of dalcetrapib with either drug resulted in enhanced decreases in LDL‐C. Whilst published data on drug–drug interactions with torcetrapib are limited, anacetrapib, which is predominantly metabolized by CYP3A4 [30–32] does not appear to inhibit or induce CYP3A4 activity [33].…”

Section: Discussionmentioning

confidence: 99%

Lack of clinically relevant drug–drug interactions when dalcetrapib is co‐administered with ezetimibe

Derks¹,

Abt²,

Phelan³

2010

Brit J Clinical Pharma

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Keywords cholesteryl ester transfer protein, dalcetrapib, drug-drug interactions, ezetimibe ---------------------------------------------------------------------- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dalcetrapib, which targets cholesteryl ester transfer protein, is currently in phase III development to evaluate its effect on the prevention of cardiovascular events. It will likely be co-administered with other lipid-modifying drugs such as the cholesterol absorption inhibitor ezetimibe. There are currently no studies on the co-administration of dalcetrapib with ezetimibe. WHAT THIS STUDY ADDS• This study showed no clinically relevant pharmacokinetic interactions when dalcetrapib was co-administered with ezetimibe. The effect of dalcetrapib on raising high-density lipoprotein cholesterol was not compromised, and there was an additive effect on low-density lipoprotein cholesterol lowering with co-administration of dalcetrapib with ezetimibe compared with ezetimibe alone. Dalcetrapib alone or co-administered with ezetimibe was not associated with an increased rate of adverse events compared with ezetimibe alone. AIMSDalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints. METHODSCo-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment. RESULTSCo-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for Cmax. Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone : LSMR 80.3 (74.6, 86.4) for AUC (0,24 h) and 88.9 (80.9, 99.9) for Cmax for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (-35.9%) was greater than with ezetimibe alone (-20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe. CONCLUSIONCo-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug.

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Effect of Diltiazem, a Moderate CYP3A Inhibitor, on the Pharmacokinetics of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein Inhibitor, in Healthy Subjects

Cited by 14 publications

References 13 publications

Anacetrapib, a Novel CETP Inhibitor: Pursuing a New Approach to Cardiovascular Risk Reduction

Anacetrapib, a Novel CETP Inhibitor: Pursuing a New Approach to Cardiovascular Risk Reduction

CETP Inhibitors: Will They Live up to Their Promise?

Lack of clinically relevant drug–drug interactions when dalcetrapib is co‐administered with ezetimibe

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