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Eric J Niesor - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the 3cl protease and sars cov 2 replication by Dalcetrapib
ACS Omega, 2021Co-Authors: Eric J Niesor, Eric Rhéaume, Anne Perez, Guy Boivin, Rong Shi, Veronique Lavoie, Nathalie Goyette, Marieeve Picard, Fouzia Laghrissithode, Jean-claude TardifAbstract:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of Dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that Dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal Dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of Dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.
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role of adenylate cyclase 9 in the pharmacogenomic response to Dalcetrapib clinical paradigm and molecular mechanisms in precision cardiovascular medicine
Circulation: Genomic and Precision Medicine, 2021Co-Authors: David Rhainds, Therese Heinonen, Eric J Niesor, Mathieu R Brodeur, Wouter J Jukema, Chris J Packard, Frank M Sacks, Scott R Wright, David D Waters, Donald M BlackAbstract:Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking Dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with Dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in Dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between Dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that Dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether Dalcetrapib will be protective in this population.
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Dalcetrapib and anacetrapib differently impact hdl structure and function in rabbits and monkeys
Journal of Lipid Research, 2017Co-Authors: Mathieu R Brodeur, David Rhainds, Eric J Niesor, Evelyne Chaput, Anne Perez, Melanie Mecteau, Genevieve Brand, Daniel Charpentier, Teodora Mihalacheavram, Eric RhéaumeAbstract:Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of Dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received Dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, Dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preβ-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of Dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment.
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Dalcetrapib and anacetrapib differently impact hdl structure and function in rabbits and monkeys
Journal of Lipid Research, 2017Co-Authors: Mathieu R Brodeur, David Rhainds, Eric J Niesor, Evelyne Chaput, Anne Perez, Melanie Mecteau, Genevieve Brand, Daniel Charpentier, Teodora Mihalacheavram, Eric RhéaumeAbstract:Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of Dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received Dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, Dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P
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statin induced decrease in atp binding cassette transporter a1 expression via microrna33 induction may counteract cholesterol efflux to high density lipoprotein
Cardiovascular Drugs and Therapy, 2015Co-Authors: Eric J Niesor, Anne Perez, Gregory G. Schwartz, Markus Abt, Andrea Stauffer, Alexandre Durrwell, Gabriela Bucklarsuchankova, Renee Benghozi, David KallendAbstract:Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBP and down-regulates ABCA1 and ABCG1 expression. We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level. In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1 μM atorvastatin increased miR33 by 33 % (P pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and Dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and Dalcetrapib. When HDL was incubated with rhCETP, addition of Dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1 μM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by Dalcetrapib. In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.
David Kallend - One of the best experts on this subject based on the ideXlab platform.
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Dalcetrapib reduces risk of new onset diabetes in patients with coronary heart disease
Diabetes Care, 2020Co-Authors: Gregory G. Schwartz, Donald M Black, Philip J Barter, David Kallend, Fouzia Laghrissithode, Christie M Ballantyne, John Jv Mcmurray, Lawrence A Leiter, Eran Leitersdorf, Stephen J NichollsAbstract:OBJECTIVE Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor Dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with Dalcetrapib 600 mg daily or placebo, beginning 4–12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to Dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68–0.88; P CONCLUSIONS In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with Dalcetrapib.
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statin induced decrease in atp binding cassette transporter a1 expression via microrna33 induction may counteract cholesterol efflux to high density lipoprotein
Cardiovascular Drugs and Therapy, 2015Co-Authors: Eric J Niesor, Anne Perez, Gregory G. Schwartz, Markus Abt, Andrea Stauffer, Alexandre Durrwell, Gabriela Bucklarsuchankova, Renee Benghozi, David KallendAbstract:Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBP and down-regulates ABCA1 and ABCG1 expression. We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level. In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1 μM atorvastatin increased miR33 by 33 % (P pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and Dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and Dalcetrapib. When HDL was incubated with rhCETP, addition of Dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1 μM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by Dalcetrapib. In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.
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Treatment of Low HDL-C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations
Lipids, 2014Co-Authors: Eric J Niesor, Darren Bentley, Gerard K Hovingh, John J. P. Kastelein, David Kallend, Erik S.g. StroesAbstract:We investigated the effect of Dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received Dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9 %) and FCH (+18.4, +12.1 %), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (−31.5, +120.9 %) and FCH (−26.6, +111.9 %), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0 %), but only campesterol was markedly increased in FCH (+25.0 %, p < 0.0001 vs. placebo). Campesterol increased with Dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.
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the effect of cholesteryl ester transfer protein inhibition on lipids lipoproteins and markers of hdl function after an acute coronary syndrome the dal acute randomized trial
European Heart Journal, 2014Co-Authors: Marc Ditmarsch, Eric J Niesor, David Kallend, Judith Anzurescabrera, Gabriela Suchankova, Ruchi Upmanyu, Valerie Lehnert, Meike Paulyevers, Ingar Holme, J StasekAbstract:Aims The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown. Methods and results The dal-ACUTE study randomized 300 patients (1 : 1) to Dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% ( P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-β1-HDL levels. The increase in total efflux with Dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C ( r = 0.46 and 0.43, respectively) rather than the increase in pre-β1-HDL ( r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-β1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. Conclusions High-density lipoprotein raised through CETP inhibition with Dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.
Jean-claude Tardif - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the 3cl protease and sars cov 2 replication by Dalcetrapib
ACS Omega, 2021Co-Authors: Eric J Niesor, Eric Rhéaume, Anne Perez, Guy Boivin, Rong Shi, Veronique Lavoie, Nathalie Goyette, Marieeve Picard, Fouzia Laghrissithode, Jean-claude TardifAbstract:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of Dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that Dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal Dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of Dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.
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abstract 11650 adcy9 inactivation improves cardiac function after myocardial infarction in absence of cholesterol ester transfer protein
Circulation, 2019Co-Authors: Marine Ferron, Eric Rhéaume, Melanie Mecteau, Genevieve Brand, Teodora Mihalacheavram, Nolwenn Merlet, Marcantoine Gillis, Yanfen Shi, Jean-claude TardifAbstract:Pharmacogenomic studies have shown that polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the effects of Dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, on cardiov...
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cetp pharmacogenomics based response to the cetp inhibitor Dalcetrapib
Arteriosclerosis Thrombosis and Vascular Biology, 2017Co-Authors: Jean-claude Tardif, David Rhainds, Eric Rhéaume, Mariepierre DubeAbstract:High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP (cholesteryl ester transfer protein) inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease. Dalcetrapib is a CETP modulator for which effects on cardiovascular outcomes were demonstrated in the dal-OUTCOMES trial to be influenced by correlated polymorphisms in the ADCY9 (adenylate cyclase type 9) gene ( P =2.4×10 −8 for rs1967309). Patients with the AA genotype at rs1967309 had a relative reduction of 39% in the risk of presenting a cardiovascular event when treated with Dalcetrapib compared with placebo (95% confidence interval, 0.41–0.92). In contrast, patients with the GG genotype had a 27% increase in risk, whereas heterozygotes (AG) presented a neutral result. Supporting evidence from the dal-PLAQUE-2 study using carotid ultrasonography revealed that the polymorphisms tested in the ADCY9 linkage disequilibrium block were associated with disease regression for patients with the protective genotype, progression for the harmful genotype, and no effect in heterozygotes ( P ≤0.05 and ≤0.01 for 10 and 3 polymorphisms, respectively) when comparing Dalcetrapib to placebo. Strikingly concordant and significant genotype-dependent effects of Dalcetrapib were also obtained for changes in high-sensitivity C-reactive protein and cholesterol efflux capacity. The Dal-GenE randomized trial is currently being conducted in patients with a recent acute coronary syndrome bearing the AA genotype at rs1967309 in the ADCY9 gene to confirm the effects of Dalcetrapib on hard cardiovascular outcomes.
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genotype dependent effects of Dalcetrapib on cholesterol efflux and inflammation concordance with clinical outcomes
Circulation-cardiovascular Genetics, 2016Co-Authors: Jean-claude Tardif, David Rhainds, Mathieu R Brodeur, Jean Gregoire, Yassamin Feroz Zada, Sylvie Provost, Marie Boule, Sonia Alem, Rene Fouodjio, Philippe L LallierAbstract:Background—Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associ...
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pharmacogenomic determinants of the cardiovascular effects of Dalcetrapib
Circulation-cardiovascular Genetics, 2015Co-Authors: Jean-claude Tardif, David Rhainds, Eric Rhéaume, Louisphilippe Lemieux Perreault, Jean Gregoire, Yassamin Feroz Zada, Geraldine Asselin, Sylvie Provost, Amina Barhdadi, Philippe L LallierAbstract:Background— Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to Dalcetrapib may vary according to patients’ genetic profile. Methods and Results— We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the Dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P =2.41×10–8), with 8 polymorphisms providing P <10–6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with Dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41–0.92). In patients with genotype GG, there was a 27% increase in events with Dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of Dalcetrapib on intima-media thickness ( P <0.05). Marker rs2238448 in ADCY9 , in linkage disequilibrium with rs1967309 ( r 2=0.8), was associated with both the effects of Dalcetrapib on intima-media thickness in dal-PLAQUE-2 ( P =0.009) and events in dal-OUTCOMES ( P =8.88×10–8; hazard ratio, 0.67; 95% confidence interval, 0.58–0.78). Conclusions— The effects of Dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene. Clinical Trial Information— URL: . Unique identifiers: [NCT00658515][1] and [NCT01059682][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00658515&atom=%2Fcirccvg%2F8%2F2%2F372.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01059682&atom=%2Fcirccvg%2F8%2F2%2F372.atom
Michael Derks - One of the best experts on this subject based on the ideXlab platform.
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no clinically relevant drug drug interactions when Dalcetrapib is co administered with a monophasic oral contraceptive microgynon 30
Principles and Practice of Constraint Programming, 2012Co-Authors: Annie M Young, Judith Anzurescabrera, Michael DerksAbstract:Dalcetrapib a cholesteryl ester transfer protein modulator under development to increase high-density lipoprotein cholesterol and potentially decrease cardiovascular risk will potentially be co-prescribed to women on oral contraceptive (OC). Objective: Assess the effect of Dalcetrapib on the pharmacokinetics and ability to suppress ovulation of Microgynon(R) 30 a representative monophasic OC. Materials and methods: A single-center randomized open-label two-period crossover study in healthy women receiving monophasic OC. Subjects received Microgynon(R) 30 (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) once daily for 21 days followed by 7 treatment-free days (run-in period) then were randomized to Microgynon(R) 30 daily for 21 days with or without Dalcetrapib 900 mg daily for Day 1 - 14. Plasma ethinylestradiol and levonorgestrel were measured on Day 14 and luteinizing hormone follicle stimulating hormone progesterone and estrogen from Day 11 - 14. The primary endpoint plasma exposure (AUC0-24 and Cmax) on Day 14 was evaluated for ethinylestradiol and levonorgestrel. Safety was monitored throughout. Results: 30 subjects were randomized. The exposure of ethinylestradiol and levonorgestrel was similar when Microgynon(R) 30 was administered with or without Dalcetrapib; for ethinylestradiol the geometric mean ratio % (90% confidence interval (CI)) for AUC0-24 and Cmax were 92 (86 - 98) and 105 (95 - 115) and for levonorgestrel 92 (88 - 96) and 93 (87 - 99) respectively. Concentrations of luteinizing hormone follicle stimulating hormone estrogen and progesterone were comparable between treatments. Conclusions: Dalcetrapib has no clinically relevant effect on the pharmacokinetics of ethinylestradiol and levonorgestrel. Contraceptive efficacy of Microgynon(R) 30 is not anticipated to be compromised by co-administration of Dalcetrapib.
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effect of Dalcetrapib a cetp modulator on non cholesterol sterol markers of cholesterol homeostasis in healthy subjects
Atherosclerosis, 2011Co-Authors: Eric J Niesor, Evelyne Chaput, Denise Blum, Michael Derks, Andreas Staempfli, David KallendAbstract:Abstract Objective Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of Dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects. Methods Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: Dalcetrapib 900mg, ezetimibe 10mg, Dalcetrapib 900mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of Dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of Dalcetrapib on cholesterol absorption. Results Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% ( p =0.001), 32% ( p p =0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% ( p =0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with Dalcetrapib, but both increased with ezetimibe alone (56–148%, p p p =0.04) and 72% ( p =0.003), respectively. Unlike torcetrapib, Dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma 3 H-cholesterol level but increased 3 H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol. Conclusion Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.
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effects of food intake on the pharmacokinetic properties of Dalcetrapib findings from three phase i single dose crossover studies in healthy volunteers
Clinical Therapeutics, 2011Co-Authors: Michael Derks, Markus Abt, Mary Phelan, Georgina Meneseslorente, Hitoshi Kawamura, Tomohiro IshikawaAbstract:Abstract Background Preclinical studies have reported that the relative bioavailability of Dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ∼60% higher when administered in the fed state compared with the fasting state. Objective This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of Dalcetrapib in healthy male subjects. Methods Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of Dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of Dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of Dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC 0–36 or AUC 0–∞ , C max ) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG. Results Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m 2 ). Dalcetrapib exposure was increased by 64% (AUC 0–36 ) and 126% (C max ) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of Dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m 2 ). When Dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean Dalcetrapib AUC 0–∞ (7400 and 7860 ng·h/mL, respectively) and C max (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC 0–∞ (14.3%–14.7%) and C max (25.5%–35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m 2 ). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC 0–∞ (34.9%) and C max (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated. Conclusions Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated.
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safety tolerability and pharmacokinetics of Dalcetrapib following single and multiple ascending doses in healthy subjects a randomized double blind placebo controlled phase i study
Clinical Drug Investigation, 2011Co-Authors: Michael Derks, Lynn Turnbull, Judith Anzurescabrera, Mary PhelanAbstract:Background: Dalcetrapib is a modulator of cholesteryl ester transfer protein (CETP) activity developed to raise levels of high-density lipoprotein cholesterol (HDL-C) with the goal of further reduction of cardiovascular events additive to standard of care alone. In clinical studies, Dalcetrapib has been shown to effectively increase levels of HDL-C with no significant safety concerns. Objective: The primary objective was to investigate the safety of single ascending and multiple ascending doses of Dalcetrapib at doses markedly greater than that intended therapeutically (600 mg/day). Secondary objectives were to investigate the pharmacokinetics/pharmacodynamics and dose proportionality of Dalcetrapib. Study Design: Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose phase I study. Healthy males (age 18–65 years, body mass index 18–?2) were randomized to four of five Dalcetrapib doses (2100,2700, 3300, 3900 or 4500 mg) or placebo, with ≥10 days washout between doses (n= 15, single ascending doses) or to Dalcetrapib (1800, 2100, 3000 or 3900 mg once daily) or placebo for 7 days (four cohorts, each n= 10, randomization 8:2, multiple ascending doses). Main Outcome Measure: Tolerability and safety were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs and 12-lead ECG recordings. Primary pharmacokinetic assessments were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) [single doses] and AUC from time zero to 24 hours (AUC24) and Cmax (multiple doses). Pharmacodynamic assessments included CETP activity and lipids (multiple dosing only). Results: Exposure increased with dose but was less than proportional to increasing dose after single dosing, although deviation from dose proportionality could not be demonstrated for Cmax. Dose proportionality was consistent following multiple doses. Steady state was modelled to have been reached by approximately 4 days, with little to no accumulation. CETP activity reduction was dose dependent (maximum −55% after 3900 mg; placebo −2.6%) at 6 hours post-dose on day 1, while HDL-C increased by 12–19% (placebo −13%) on day 8 following treatment with 1800−3900 mg/day for 7 days. All AEs were mild or moderate in intensity and there were no serious AEs, deaths or withdrawals due to AEs. No clinically relevant effects on laboratory parameters, cardiac parameters or vital signs were noted. Conclusion: Single-dose Dalcetrapib up to 4500 mg and multiple doses up to 3900 mg were generally safe and well tolerated.
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lack of clinically relevant drug drug interactions when Dalcetrapib is co administered with ezetimibe
British Journal of Clinical Pharmacology, 2010Co-Authors: Michael Derks, Markus Abt, Mary PhelanAbstract: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. AIMS Dalcetrapib, 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. METHODS Co-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. RESULTS Co-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. CONCLUSION Co-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.
Markus Abt - One of the best experts on this subject based on the ideXlab platform.
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statin induced decrease in atp binding cassette transporter a1 expression via microrna33 induction may counteract cholesterol efflux to high density lipoprotein
Cardiovascular Drugs and Therapy, 2015Co-Authors: Eric J Niesor, Anne Perez, Gregory G. Schwartz, Markus Abt, Andrea Stauffer, Alexandre Durrwell, Gabriela Bucklarsuchankova, Renee Benghozi, David KallendAbstract:Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBP and down-regulates ABCA1 and ABCG1 expression. We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level. In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1 μM atorvastatin increased miR33 by 33 % (P pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and Dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and Dalcetrapib. When HDL was incubated with rhCETP, addition of Dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1 μM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by Dalcetrapib. In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.
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statin induced decrease in abca1 expression via mir33 induction may counteract cholesterol efflux by high density lipoproteins raised with the cholesteryl ester transfer protein modulator Dalcetrapib
Journal of the American College of Cardiology, 2013Co-Authors: Eric J Niesor, Markus Abt, Renee Benghozi, Gabriela Suchankova, Gregory Schwartz, David KallendAbstract:Reverse cholesterol transport is believed to be an important function of high–density lipoprotein (HDL). HDL–cholesterol from patients treated with the cholesteryl ester transfer protein (CETP) modulator Dalcetrapib has been shown to increase cholesterol efflux in vitro in the absence of statin
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effects of Dalcetrapib in patients with a recent acute coronary syndrome
The New England Journal of Medicine, 2012Co-Authors: Gregory G. Schwartz, Philip J Barter, David Kallend, Markus Abt, Christie M Ballantyne, Anders G Olsson, Jochen Brumm, Bernard R Chaitman, I Holme, Lawrence A LeiterAbstract:Background In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. Methods We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor Dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. Results At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 ...
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safety and efficacy of Dalcetrapib on atherosclerotic disease using novel non invasive multimodality imaging dal plaque a randomised clinical trial
The Lancet, 2011Co-Authors: Zahi A. Fayad, David Kallend, Markus Abt, Tracy Burgess, Venkatesh Mani, Mark Woodward, Valentin Fuster, Christie M Ballantyne, Evan A SteinAbstract:Summary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to Dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or Dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the Dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given Dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm 2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the Dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of Dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of Dalcetrapib need to be analysed. Funding F Hoffmann-La Roche Ltd.
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effects of food intake on the pharmacokinetic properties of Dalcetrapib findings from three phase i single dose crossover studies in healthy volunteers
Clinical Therapeutics, 2011Co-Authors: Michael Derks, Markus Abt, Mary Phelan, Georgina Meneseslorente, Hitoshi Kawamura, Tomohiro IshikawaAbstract:Abstract Background Preclinical studies have reported that the relative bioavailability of Dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ∼60% higher when administered in the fed state compared with the fasting state. Objective This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of Dalcetrapib in healthy male subjects. Methods Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of Dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of Dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of Dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC 0–36 or AUC 0–∞ , C max ) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG. Results Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m 2 ). Dalcetrapib exposure was increased by 64% (AUC 0–36 ) and 126% (C max ) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of Dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m 2 ). When Dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean Dalcetrapib AUC 0–∞ (7400 and 7860 ng·h/mL, respectively) and C max (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC 0–∞ (14.3%–14.7%) and C max (25.5%–35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m 2 ). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC 0–∞ (34.9%) and C max (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated. Conclusions Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated.
