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Julian Hardy McLain, Andrew Jacob Alsterda, Rohit R Arora
The cholesteryl ester transfer protein (CETP) is a plasma protein that plays an important role in the transfer of lipids between plasma lipoproteins. The CETP inhibitors have been widely studied as a pharmacologic therapy to target plasma cholesterol in order to reduce the risk of atherosclerotic cardiovascular disease . Using CETP inhibitors as cholesterol modifiers was based on the genetic research that found correlations between CETP activity and cholesterol levels. Although CETP inhibitors are successful at altering targeted cholesterol markers, recent phase 3 outcome trials have shown limited benefit on cardiovascular outcomes when combined with the current standard of care...
August 10, 2016: Journal of Cardiovascular Pharmacology and Therapeutics
Shizuya Yamashita, Yuji Matsuzawa
PURPOSE OF REVIEW: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. RECENT FINDINGS: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events...
October 2016: Current Opinion in Lipidology
David S Small, Jane Royalty, Ellen A Cannady, Christine Hale, Ming-Dauh Wang, Delyn Downs, Jeffrey G Suico
STUDY OBJECTIVE: To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease. DESIGN: Open-label, two-treatment, two-period, fixed-sequence crossover study. SETTING: Clinical research unit. SUBJECTS: Thirty-four healthy subjects. INTERVENTION: In period 1, subjects received a single oral dose of evacetrapib 130 mg on day 1, followed by 7 days of analysis for evacetrapib plasma concentrations...
July 2016: Pharmacotherapy
Stephen J Nicholls, Giacomo Ruotolo, H Bryan Brewer, Ming-Dauh Wang, Liping Liu, Mark B Willey, Mark A Deeg, Kathryn A Krueger, Steven E Nissen
BACKGROUND: Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk. OBJECTIVES: To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)-containing lipoproteins in mildly hypercholesterolemic patients. METHODS: VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials...
May 2016: Journal of Clinical Lipidology
T D Filippatos, E Klouras, F Barkas, M Elisaf
INTRODUCTION: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction. AREAS COVERED: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review. Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels)...
August 2016: Expert Review of Cardiovascular Therapy
David S Small, Wei Zhang, Jane Royalty, Ellen A Cannady, Delyn Downs, Demetrio Ortega, Jeffrey G Suico
PURPOSE: The aim of this study is to investigate the effect of hepatic or renal impairment on the pharmacokinetics of a single 130-mg evacetrapib dose. METHODS: Two open-label, parallel-design studies in males and females with normal hepatic function or Child-Pugh mild, moderate, or severe hepatic impairment, or with normal renal function or severe renal impairment. Non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time data. Evacetrapib safety and tolerability were assessed...
May 2016: European Journal of Clinical Pharmacology
Stephen J Nicholls, A Michael Lincoff, Philip J Barter, H Bryan Brewer, Keith A A Fox, C Michael Gibson, Christopher Grainger, Venugopal Menon, Gilles Montalescot, Daniel Rader, Alan R Tall, Ellen McErlean, Jeffrey Riesmeyer, Burkhard Vangerow, Giacomo Ruotolo, Govinda J Weerakkody, Steven E Nissen
BACKGROUND: Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease...
December 2015: American Heart Journal
Ellen A Cannady, Aktham Aburub, Chris Ward, Chris Hinds, Boris Czeskis, Kenneth Ruterbories, Jeffrey G Suico, Jane Royalty, Demetrio Ortega, Brian W Pack, Syeda L Begum, William F Annes, Qun Lin, David S Small
This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated...
May 30, 2016: Journal of Labelled Compounds & Radiopharmaceuticals
Amirhossein Sahebkar, Luis E Simental-Mendía, Fernando Guerrero-Romero, Jonathan Golledge, Gerald F Watts
BACKGROUND: Evacetrapib, a new cholesteryl ester transfer protein inhibitor, is being investigated as a potential therapeutic option for reducing cardiovascular events through increasing high-density lipoprotein cholesterol (HDL-C) concentrations. How evacetrapib affects other lipid parameters is less certain. The present study aimed to estimate the effect of evacetrapib on plasma lipid concentrations and to assess its safety through a systematic review and meta-analysis of randomized controlled trials...
2016: Current Pharmaceutical Design
Stephen J Nicholls, Giacomo Ruotolo, H Bryan Brewer, John P Kane, Ming-Dauh Wang, Kathryn A Krueger, Steven J Adelman, Steven E Nissen, Daniel J Rader
BACKGROUND: Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited. OBJECTIVES: This study assessed the impact of evacetrapib, statins, or combination therapy on CEC...
November 17, 2015: Journal of the American College of Cardiology
Ellen A Cannady, Ming-Dauh Wang, Stuart Friedrich, Jessica L F Rehmel, Ping Yi, David S Small, Wei Zhang, Jeffrey G Suico
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...
October 2015: Pharmacology Research & Perspectives
V Scott Sharp, Megan A Gokey, Chad N Wolfe, Gregory A Rener, Mary R Cooper
Using multiple HPLC chromatographic modes and various chiral columns in the context of an automated screening system, a potential separation was initially identified for the methyl ester of evacetrapib and its stereoisomers using an immobilized polysaccharide-based HPLC column. The bonded nature of this column, the Chiralpak(®) IC, allows for enhanced separation development with a diverse solvent range not amenable to standard coated chiral stationary phases. The ternary eluent system ultimately identified provided isomer resolutions not obtainable via the more established hexane/alcohol or polar organic chromatographic modes...
October 16, 2015: Journal of Chromatography. A
Ellen A Cannady, Jeffrey G Suico, Ming-Dauh Wang, Stuart Friedrich, Jessica R F Rehmel, Stephen J Nicholls, Kathryn A Krueger
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...
December 2015: British Journal of Clinical Pharmacology
David S Small, Wei Zhang, Jane Royalty, Ellen A Cannady, Delyn Downs, Stuart Friedrich, Jeffrey G Suico
PURPOSE: To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants. METHODS: This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for evacetrapib concentrations and pharmacokinetic parameter estimates including area under the concentration-time curve during a dosing interval (AUCτ), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated...
September 2015: Journal of Cardiovascular Pharmacology and Therapeutics
David S Small, Alice Ban Ke, Stephen D Hall, Nathan Mantlo, Matthew Rotelli, Stuart Friedrich
Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition...
July 2015: Journal of Clinical Pharmacology
Sophie Colin, Giulia Chinetti-Gbaguidi, Jan A Kuivenhoven, Bart Staels
Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases...
2015: Handbook of Experimental Pharmacology
Hiroshi Mabuchi, Atsushi Nohara, Akihiro Inazu
Epidemiologic studies have shown that low-density lipoprotein cholesterol (LDL-C) is a strong risk factor, whilst high-density lipoprotein cholesterol (HDL-C) reduces the risk of coronary heart disease (CHD). Therefore, strategies to manage dyslipidemia in an effort to prevent or treat CHD have primarily attempted at decreasing LDL-C and raising HDL-C levels. Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL and LDL. We have published the first report indicating that a group of Japanese patients who were lacking CETP had extremely high HDL-C levels, low LDL-C levels and a low incidence of CHD...
November 2014: Molecules and Cells
Matilda Florentin, Michael S Kostapanos, Anastazia Kei, Moses S Elisaf
INTRODUCTION: Hypercholesterolaemia is a significant risk factor for cardiovascular disease (CVD), a major cause of morbidity and mortality. Up to now, the appropriate management has been aggressive hypolipidaemic therapy, particularly with statins, aiming at certain low-density lipoprotein cholesterol (LDL-C) levels for each patient population. This strategy has reduced CVD-related morbidity and mortality. However, many cardiovascular events still occur, probably as a consequence of lipid disorders other than high LDL-C concentration or other risk factors...
December 2014: Expert Opinion on Emerging Drugs
Amirhossein Sahebkar, Gerard T Chew, Gerald F Watts
Elevated plasma triglyceride (TG) concentrations are associated with an increased risk of atherosclerotic cardiovascular disease (CVD), hepatic steatosis and pancreatitis. Existing pharmacotherapies, such as fibrates, n-3 polyunsaturated fatty acids (PUFAs) and niacin, are partially efficacious in correcting elevated plasma TG. However, several new TG-lowering agents are in development that can regulate the transport of triglyceride-rich lipoproteins (TRLs) by modulating key enzymes, receptors or ligands involved in their metabolism...
October 2014: Progress in Lipid Research
Melvin George, Sandhiya Selvarajan, Rajaram Muthukumar, Shanmugam Elangovan
Dyslipidaemia is a critical risk factor for the development of cardiovascular complications such as ischemic heart disease and stroke. Although statins are effective anti-dyslipidemic drugs, their usage is fraught with issues such as failure of adequate lipid control in 30% of cases and intolerance in select patients. The limited potential of other alternatives such as fibrates, bile acid sequestrants and niacin has spurred the search for novel drug molecules with better efficacy and safety. CETP inhibitors such as evacetrapib and anacetrapib have shown promise in raising HDL besides LDL lowering property...
January 2015: Journal of Cardiovascular Pharmacology and Therapeutics
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