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Sukrut Shah - One of the best experts on this subject based on the ideXlab platform.

  • a multiregional randomized evaluation of the lipid modifying efficacy and tolerability of Anacetrapib added to ongoing statin therapy in patients with hypercholesterolemia or low high density lipoprotein cholesterol
    American Journal of Cardiology, 2017
    Co-Authors: Christie M Ballantyne, Sukrut Shah, Tanya B Ashraf, Aditi Sapre, Sandra C Tobias, Tayfun Sahin, Yugang Dong, Wayne Hueyheng Sheu, Dukhyun Kang, P Rossi
    Abstract:

    This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of Anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to Anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of Anacetrapib. Treatment with Anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval -42.5, -31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the Anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with Anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.

  • lipid modifying efficacy and tolerability of Anacetrapib added to ongoing statin therapy in patients with hypercholesterolemia or low high density lipoprotein cholesterol
    American Journal of Cardiology, 2017
    Co-Authors: Christie M Ballantyne, Sukrut Shah, Amy O Johnsonlevonas, Uma Kher, Tanya B Ashraf, John A Hunter, Geraldine G Gill, Michael D Cressman, Yale B Mitchel
    Abstract:

    To assess the effects of Anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160 mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40 mg/dl, were randomized 1:1:1, stratified by background therapy use, to Anacetrapib 100 mg (n = 153), Anacetrapib 25 mg (n = 152), or placebo (n = 154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of Anacetrapib. Both doses of Anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the Anacetrapib 25 mg, 100 mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with Anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.

  • Anacetrapib as lipid modifying therapy in patients with heterozygous familial hypercholesterolaemia realize a randomised double blind placebo controlled phase 3 study
    The Lancet, 2015
    Co-Authors: John J P Kastelein, Sukrut Shah, Joost Besseling, Jean Bergeron, G Langslet, Kees G Hovingh, Naab Alsaady, Michiel Koeijvoets, John Hunter, Amy O Johnsonlevonas
    Abstract:

    Summary Background Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of Anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18–80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral Anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. Findings Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to Anacetrapib and 102 to placebo. One patient in the Anacetrapib group did not receive the drug. At week 52, Anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI −39·5 to −32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [–1·2 to 8·6], with a difference in percentage change between Anacetrapib and placebo of −39·7% (95% CI −45·7 to −33·7; p vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). Interpretation In patients with heterozygous familial hypercholesterolaemia, treatment with Anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. Funding Merck & Co, Inc

  • effects of Anacetrapib on plasma lipids in specific patient subgroups in the define determining the efficacy and tolerability of cetp inhibition with Anacetrapib trial
    Journal of Clinical Lipidology, 2015
    Co-Authors: Eliot A. Brinton, Sukrut Shah, Hayes M Dansky, Michael H Davidson, Christopher P Cannon, Antonio M. Gotto, Uma Kher, Tanya B Ashraf, Christine Mccrary Sisk, Yale B Mitchel
    Abstract:

    Background In the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with Anacetrapib (DEFINE) trial, Anacetrapib added to statin produced robust low-density lipoprotein cholesterol (LDL-C)-lowering and high-density lipoprotein cholesterol (HDL-C)-raising vs placebo in patients with coronary heart disease (CHD). Predictors of the degree of LDL-C and HDL-C responses to Anacetrapib, however, are poorly understood. Objective Lipid effects of Anacetrapib in patient subgroups within the DEFINE trial (clinicaltrials.gov: NCT00685776) are reported. Methods The percent of placebo-corrected changes from baseline for LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) and HDL-C after 24 weeks of Anacetrapib 100 mg/day were compared among patients by age, gender, race, diabetes status, type of concomitant statin with or without other lipid therapies, and baseline HDL-C, Fc-LDL-C, and triglyceride (TG) levels. Results Percent decreases in Fc-LDL-C and increases in HDL-C with Anacetrapib were similar (magnitude of difference generally Conclusion Effects of Anacetrapib on Fc-LDL-C and HDL-C were generally comparable across subgroups, including being relatively independent of baseline Fc-LDL-C, HDL-C, or TG levels. The clinical impact of the lipid-modifying effects of Anacetrapib is being evaluated in the cardiovascular disease outcomes trial, Randomized EValuation of the Effects of Anacetrapib though Lipid-modification (REVEAL).

  • abstract 9613 randomized evaluation of Anacetrapib lipid modifying therapy in patients with heterozygous familial hypercholesterolemia realize study
    Circulation, 2014
    Co-Authors: John J P Kastelein, Sukrut Shah, Joost Besseling, Jean Bergeron, G Langslet, Kees G Hovingh, Naab Alsaady, Michiel Koeijvoets, John Hunter, Amy O Johnsonlevonas
    Abstract:

    Introduction: Anacetrapib, a cholesteryl ester transfer protein inhibitor, has been shown to robustly reduce atherogenic lipoproteins including low-density lipoprotein cholesterol (LDL-C), Apo B and raise high-density lipoprotein cholesterol (HDL-C) as well as ApoA1. Hypothesis: This 1-year, Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy and safety profile of Anacetrapib added to optimized LDL-C lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH). Methods: Patients with a genotype-confirmed or clinical diagnosis of HeFH, treated with an optimal dose of statin ± other lipid-modifying medication(s) and having an LDL-C ≥100 mg/dL without history of cardiovascular disease or LDL-C ≥70 mg/dL with a history of CVD were randomized in a ratio of 2:1 to Anacetrapib 100 mg (n=204) or placebo (n=102) for 52 weeks followed by a 12-week reversal phase. The primary end points were the percent change from baseline in LDL-C (beta-quantification method) and the safety profile of Anacetrapib. This trial is registered in ClinicalTrials.gov, #NCT01524289. Results: A total of 306 patients were enrolled at 25 sites in 9 countries. At baseline, most patients were on high-dose statin therapy and >70% also were on ezetimibe. Baseline LDL-C and HDL-C were 129.4 and 53.3 mg/dL, respectively. At Week 52, Anacetrapib vs. placebo significantly reduced LDL-C by 39.7% and increased HDL-C by 102.1% (p Conclusion: In patients with HeFH, treatment with Anacetrapib for 1 year was generally well tolerated and resulted in substantial reductions in LDL-C and increases in HDL-C.

Rajesh Krishna - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics and pharmacodynamics of Anacetrapib in black and white healthy subjects
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Rajesh Krishna, Josee Cote, John A Wagner, David E Gutstein, Yang Liu, Ferdous Gheyas, Christy Corr
    Abstract:

    Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of Anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks (-21.2%) relative to whites (-39.0%). In contrast, there were no apparent race-related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of Anacetrapib independent of pharmacokinetics.

  • pharmacokinetics and pharmacodynamics of Anacetrapib following single doses in healthy young japanese and white male subjects
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Rajesh Krishna, Josee Cote, John A Wagner, Yang Liu, Ferdous Gheyas, Omar F Laterza, Jon L Ruckle, Andrew Denker
    Abstract:

    Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of Anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg Anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary Anacetrapib levels were all below quantitation limits. Plasma concentrations of Anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of Anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.

  • chronic administration of Anacetrapib is associated with accumulation in adipose and slow elimination
    Clinical Pharmacology & Therapeutics, 2017
    Co-Authors: Rajesh Krishna, Josee Cote, Robert O Blaustein, Yang Liu, Ferdous Gheyas, Brittany Walker, David Hagen, Akshita Chawla, David E Gutstein
    Abstract:

    Anacetrapib is a novel cholesteryl-ester transfer protein (CETP) inhibitor in late-stage clinical development, shown in preceding clinical trials to have residual pharmacological activity after prolonged washout after chronic dosing. Preclinical findings suggest that white adipose tissue is a potential depot and that accumulation into adipose tissue governs the long-term kinetics of Anacetrapib in mice. A phase I study performed to test this hypothesis in humans revealed that plasma exposure was correlated with fat content in food administered with the drug. Plasma concentrations of Anacetrapib seemed to reach plateau faster than adipose concentrations. Anacetrapib continued to accumulate in adipose during the treatment period despite apparent plateau in plasma with only minimal decline in adipose levels up to 1 year postdose. Because of its high lipophilicity, Anacetrapib partitions into adipose tissue, this likely forms a drug reservoir that, in turn, contributes to the long residence time of the drug in plasma.

  • lack of a meaningful effect of Anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Rajesh Krishna, Josee Cote, Daria Stypinski, Amit Garg, Melissa Ali, Andrea Maes, Bruce Degroot, Yang Liu, Sandra M Connolly, John A Wagner
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between Anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of Anacetrapib, indicating that Anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with Anacetrapib. AIM Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg CoumadinTM) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of Anacetrapib (1 × 100 mg) beginning on day −14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All Anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + Anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC(0–∞) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(−) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + Anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin Cmax were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(−) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + Anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC(0–168 h) was 0.93 (0.89, 0.96). CONCLUSION The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of Anacetrapib, indicating that Anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with Anacetrapib.

  • Anacetrapib a novel cetp inhibitor pursuing a new approach to cardiovascular risk reduction
    Clinical Pharmacology & Therapeutics, 2012
    Co-Authors: David E Gutstein, Yale B Mitchel, Rajesh Krishna, Howard K Surks, Hayes M Dansky, J Arena, Douglas G Johns, Sonia Shah, John A Wagner
    Abstract:

    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.

Yale B Mitchel - One of the best experts on this subject based on the ideXlab platform.

  • lipid modifying efficacy and tolerability of Anacetrapib added to ongoing statin therapy in patients with hypercholesterolemia or low high density lipoprotein cholesterol
    American Journal of Cardiology, 2017
    Co-Authors: Christie M Ballantyne, Sukrut Shah, Amy O Johnsonlevonas, Uma Kher, Tanya B Ashraf, John A Hunter, Geraldine G Gill, Michael D Cressman, Yale B Mitchel
    Abstract:

    To assess the effects of Anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160 mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40 mg/dl, were randomized 1:1:1, stratified by background therapy use, to Anacetrapib 100 mg (n = 153), Anacetrapib 25 mg (n = 152), or placebo (n = 154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of Anacetrapib. Both doses of Anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the Anacetrapib 25 mg, 100 mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with Anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.

  • effects of Anacetrapib on plasma lipids in specific patient subgroups in the define determining the efficacy and tolerability of cetp inhibition with Anacetrapib trial
    Journal of Clinical Lipidology, 2015
    Co-Authors: Eliot A. Brinton, Sukrut Shah, Hayes M Dansky, Michael H Davidson, Christopher P Cannon, Antonio M. Gotto, Uma Kher, Tanya B Ashraf, Christine Mccrary Sisk, Yale B Mitchel
    Abstract:

    Background In the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with Anacetrapib (DEFINE) trial, Anacetrapib added to statin produced robust low-density lipoprotein cholesterol (LDL-C)-lowering and high-density lipoprotein cholesterol (HDL-C)-raising vs placebo in patients with coronary heart disease (CHD). Predictors of the degree of LDL-C and HDL-C responses to Anacetrapib, however, are poorly understood. Objective Lipid effects of Anacetrapib in patient subgroups within the DEFINE trial (clinicaltrials.gov: NCT00685776) are reported. Methods The percent of placebo-corrected changes from baseline for LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) and HDL-C after 24 weeks of Anacetrapib 100 mg/day were compared among patients by age, gender, race, diabetes status, type of concomitant statin with or without other lipid therapies, and baseline HDL-C, Fc-LDL-C, and triglyceride (TG) levels. Results Percent decreases in Fc-LDL-C and increases in HDL-C with Anacetrapib were similar (magnitude of difference generally Conclusion Effects of Anacetrapib on Fc-LDL-C and HDL-C were generally comparable across subgroups, including being relatively independent of baseline Fc-LDL-C, HDL-C, or TG levels. The clinical impact of the lipid-modifying effects of Anacetrapib is being evaluated in the cardiovascular disease outcomes trial, Randomized EValuation of the Effects of Anacetrapib though Lipid-modification (REVEAL).

  • evaluation of lipids drug concentration and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor Anacetrapib in patients with or at high risk for coronary heart disease
    American Journal of Cardiology, 2014
    Co-Authors: Antonio M. Gotto, Sukrut Shah, Hayes M Dansky, Eliot A. Brinton, Michael H Davidson, Christopher P Cannon, Uma Kher, Sanskruti Vaidya, Jennifer Moon, Yale B Mitchel
    Abstract:

    The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with Anacetrapib. The cholesteryl ester transfer protein inhibitor Anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to Anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma Anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of Anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of Anacetrapib in plasma 2.5 to 4 years after the last Anacetrapib dose. In conclusion, after the cessation of active treatment, Anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

  • measurement of ldl c after treatment with the cetp inhibitor Anacetrapib
    Journal of Lipid Research, 2013
    Co-Authors: Michael H Davidson, Elizabeth T Leary, Sukrut Shah, Michael Stepanavage, Eliot A. Brinton, Christopher P Cannon, Antonio M. Gotto, Philip J Barter, Yale B Mitchel
    Abstract:

    Estimation of low-density lipoprotein cholesterol (LDL-C) using the Friedewald (FR) formula is often inaccu- rate when triglycerides are elevated or VLDL particle compo- sition is altered. We hypothesized that LDL-C estimation by the FR formula and other measurement methods might also be inaccurate in individuals treated with a cholesteryl ester transfer protein (CETP) inhibitor. An assay comparison study was conducted using pre and posttreatment serum samples from 280 of the 811 patients treated with the CETP inhibitor Anacetrapib in the DEFINE study ( d etermining the ef fi cacy and tolerability of CETP in hibition with anac e trapib). After 24 weeks of treatment with Anacetrapib, mean LDL-C values by FR formula, Roche direct method (RDM) and Genzyme direct method (GDM) deviated from that measured by the -quantifi cation (BQ) reference method by -12.2 ± 7.5, -10.2 ± 6.6, -10.8 ± 8.8 mg/dl, respectively. After treatment with Anacetrapib, the FR formula and detergent-based direct methods provided lower LDL-C values than those obtained by the BQ reference method. The bias by the FR formula appeared to be due to an overestimation of VLDL-C by the TG/5 component of the formula. Evaluation of the clinical signifi cance of these fi ndings awaits comprehensive lipid and cardiovascular outcome data from ongoing Phase III clinical studies of Anacetrapib. —Davidson, M., S. X. Liu, P. Barter, E. A. Brinton, C. P. Cannon, A. M. Gotto, Jr., E. T. Leary, S. Shah, M. Stepanavage, Y. Mitchel, and H. M. Dansky. Measurement of LDL-C after treatment with the CETP inhibitor Anacetrapib. J. Lipid Res. 2013. 54: 467-472.

  • Anacetrapib a novel cetp inhibitor pursuing a new approach to cardiovascular risk reduction
    Clinical Pharmacology & Therapeutics, 2012
    Co-Authors: David E Gutstein, Yale B Mitchel, Rajesh Krishna, Howard K Surks, Hayes M Dansky, J Arena, Douglas G Johns, Sonia Shah, John A Wagner
    Abstract:

    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.

John A Wagner - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics and pharmacodynamics of Anacetrapib in black and white healthy subjects
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Rajesh Krishna, Josee Cote, John A Wagner, David E Gutstein, Yang Liu, Ferdous Gheyas, Christy Corr
    Abstract:

    Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of Anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks (-21.2%) relative to whites (-39.0%). In contrast, there were no apparent race-related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of Anacetrapib independent of pharmacokinetics.

  • pharmacokinetics and pharmacodynamics of Anacetrapib following single doses in healthy young japanese and white male subjects
    The Journal of Clinical Pharmacology, 2018
    Co-Authors: Rajesh Krishna, Josee Cote, John A Wagner, Yang Liu, Ferdous Gheyas, Omar F Laterza, Jon L Ruckle, Andrew Denker
    Abstract:

    Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of Anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg Anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary Anacetrapib levels were all below quantitation limits. Plasma concentrations of Anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of Anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.

  • cetp cholesteryl ester transfer protein inhibition with Anacetrapib decreases production of lipoprotein a in mildly hypercholesterolemic subjects
    Arteriosclerosis Thrombosis and Vascular Biology, 2017
    Co-Authors: Tiffany Thomas, John A Wagner, Rajasekhar Ramakrishnan, Patricia Jumes, Yang Liu, Wahida Karmally, Haihong Zhou, Stephen Holleran, Brian K Hubbard, Stephen F Previs
    Abstract:

    Objective— Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, Anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by Anacetrapib. Approach and Results— We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of Anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus Anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus Anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of Anacetrapib treatment. We performed stable isotope kinetic studies using 2 H 3 -leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9–108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4–121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% ( P ≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. Conclusions— Anacetrapib reduces Lp(a) levels by decreasing its production. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.

  • single therapeutic and supratherapeutic doses of Anacetrapib a cholesteryl ester transfer protein inhibitor do not prolong the qtcf interval in healthy volunteers
    The Journal of Clinical Pharmacology, 2014
    Co-Authors: Brett Lauring, Amy O Johnsonlevonas, John A Wagner, Yang Liu, Patrick Larson, Allison Moreau, Frank H Farmer, Eseng Lai
    Abstract:

    Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of Anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of Anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between Anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for Anacetrapib 100 and 800 mg were <5 msec at every time point. In conclusion, single doses of Anacetrapib 100 and 800 mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects.

  • abstract 118 the effect of cetp inhibition with Anacetrapib on the metabolism of pcsk9
    Arteriosclerosis Thrombosis and Vascular Biology, 2013
    Co-Authors: John S Millar, John A Wagner, David E Gutstein, Michael E Lassman, Patricia Jumes, Gissette Reyessoffer, Henry N Ginsberg, Hashmi Rafeek, Allen Wong, Daniel J. Rader
    Abstract:

    Introduction Inhibition of CETP activity with Anacetrapib has been associated with a significant reduction in low density lipoprotein (LDL)-cholesterol (C) levels both as a monotherapy and in combination with a statin. We recently reported that this reduction in LDL-C is due to a significant increase in the fractional clearance rate (FCR) of LDL apoB. One potential mechanism by which Anacetrapib could influence LDL apoB clearance is through effects on PCSK9 metabolism. We conducted kinetic studies on PCSK9 to determine if a change in the metabolism of PCSK9 is responsible for the reduction in LDL-C levels following treatment with Anacetrapib. Methods Moderately hyperlipidemic volunteers (n=39) were enrolled in a fixed-sequence study: 75% were on atorvastatin (20mg/day) plus placebo and 25% were on double placebo for four weeks. Following this baseline period subjects added Anacetrapib (100 mg/day) to their background treatment for 8 weeks. Studies using D3 leucine tracer were performed at the end of each treatment period to determine the kinetics PCSK9. Results Statin treated subjects had lower LDL-C levels (84 vs 118 mg/dL) and higher PCSK9 levels (234 vs. 208 ng/mL) at baseline than subjects on placebo. The difference in PCSK9 was due to a higher PCSK9 production rate (PR) (19.7 vs. 16.7 ug/kg/day) but similar PCSK9 FCR (1.87 vs. 1.78 pools/day). Adding Anacetrapib to background treatment was associated with a significant reduction in LDL cholesterol (~ -35%) and apoB levels (~ 20%) in both panels. Anacetrapib had no significant effect on PCSK9 levels in either of the background treatment groups. Consistent with the lack of change in PCSK9 levels, there was no effect of Anacetrapib on the PR (18.1 vs. 19.3 ug/kg/day) or FCR of PCSK9 (1.82 vs. 1.93 pools/day). Conclusion These results indicate that in our study population the increase in LDL FCR observed in response to Anacetrapib treatment is not likely to be related to changes in the metabolism of PCSK9.

Amy O Johnsonlevonas - One of the best experts on this subject based on the ideXlab platform.

  • lipid modifying efficacy and tolerability of Anacetrapib added to ongoing statin therapy in patients with hypercholesterolemia or low high density lipoprotein cholesterol
    American Journal of Cardiology, 2017
    Co-Authors: Christie M Ballantyne, Sukrut Shah, Amy O Johnsonlevonas, Uma Kher, Tanya B Ashraf, John A Hunter, Geraldine G Gill, Michael D Cressman, Yale B Mitchel
    Abstract:

    To assess the effects of Anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160 mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40 mg/dl, were randomized 1:1:1, stratified by background therapy use, to Anacetrapib 100 mg (n = 153), Anacetrapib 25 mg (n = 152), or placebo (n = 154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of Anacetrapib. Both doses of Anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the Anacetrapib 25 mg, 100 mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with Anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.

  • efficacy and safety of the cholesteryl ester transfer protein inhibitor Anacetrapib in japanese patients with heterozygous familial hypercholesterolemia
    Atherosclerosis, 2016
    Co-Authors: Hidenori Arai, Tamio Teramoto, Hiroyuki Daida, Katsunori Ikewaki, Yuko Maeda, Mariko Nakagomi, Masayoshi Shirakawa, Taro Kakikawa, Hirotaka Numaguchi, Amy O Johnsonlevonas
    Abstract:

    Abstract Background and aims This multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy/safety profile of Anacetrapib 100 mg added to ongoing statin ± other lipid-modifying therapies (LMT) in Japanese patients with heterozygous familial hypercholesterolemia (HeFH). Methods Patients 18–80 years with a genotype-confirmed/clinical diagnosis of HeFH who were on a stable dose of statin ± other LMT for ≥6 weeks and with an LDL-C concentration ≥100 mg/dL were randomized to Anacetrapib 100 mg (n = 34) or placebo (n = 34) for 12 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were percent change from baseline in LDL-C (beta-quantification method [BQ]) and safety/tolerability. Results At Week 12, treatment with Anacetrapib reduced LDL-C (BQ) compared to placebo and resulting in a between-group difference of 29.8% (95% CI: −38.6 to −21.0; p  Conclusions In Japanese patients with HeFH, treatment with Anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL-C and increases in HDL-C and was well tolerated. (ClinicalTrials.gov NCT01824238)

  • Anacetrapib as lipid modifying therapy in patients with heterozygous familial hypercholesterolaemia realize a randomised double blind placebo controlled phase 3 study
    The Lancet, 2015
    Co-Authors: John J P Kastelein, Sukrut Shah, Joost Besseling, Jean Bergeron, G Langslet, Kees G Hovingh, Naab Alsaady, Michiel Koeijvoets, John Hunter, Amy O Johnsonlevonas
    Abstract:

    Summary Background Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of Anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18–80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral Anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. Findings Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to Anacetrapib and 102 to placebo. One patient in the Anacetrapib group did not receive the drug. At week 52, Anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI −39·5 to −32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [–1·2 to 8·6], with a difference in percentage change between Anacetrapib and placebo of −39·7% (95% CI −45·7 to −33·7; p vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). Interpretation In patients with heterozygous familial hypercholesterolaemia, treatment with Anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. Funding Merck & Co, Inc

  • changes in ldl particle concentrations after treatment with the cholesteryl ester transfer protein inhibitor Anacetrapib alone or in combination with atorvastatin
    Journal of Clinical Lipidology, 2015
    Co-Authors: Ronald M Krauss, Yang Liu, Amy O Johnsonlevonas, Cathy Anne Pinto, Hayes M Dansky
    Abstract:

    Objectives Our aim was to assess the effects of the cholesteryl ester transfer protein (CETP) inhibitor Anacetrapib and atorvastatin, both as monotherapy and in combination, on particle concentrations of low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins in dyslipidemic patients. Background Although increases in high-density lipoproteins with CETP inhibition are well-documented, effects on atherogenic lipoprotein particle subclasses in dyslipidemic patients have not been extensively characterized. Methods Ion mobility was performed on stored plasma samples collected from patients before and after treatment with Anacetrapib alone (150 and 300 mg/d) or in combination with atorvastatin (20 mg/d) in a previously conducted 8-week phase IIb study. Results Anacetrapib produced significant placebo-adjusted reductions of total LDL particles and all subfractions except for increases in very small LDL 4a and 4b. Atorvastatin reduced all LDL subfractions except LDL 4b. Results were generally additive for Anacetrapib + atorvastatin. For patients treated with Anacetrapib, the placebo-adjusted reduction in LDL 3a was attenuated and there was an increase in LDL 3b and 4a for those with low vs high triglyceride (TG) levels. For the atorvastatin alone vs placebo treatment comparison, there were small reductions in LDL 3a, 3b, and 4a for those with low vs high TG levels. Conclusions Anacetrapib and atorvastatin produced similar reductions from baseline in total LDL particles, but did not have comparable effects on all LDL particle subfractions, and neither drug reduced the smallest LDL 4b particles. The clinical significance of these changes and the differential effects on very small LDL 4a in patients with higher vs lower TG remain to be determined (clinicaltrials.gov, NCT00325455).

  • abstract 9613 randomized evaluation of Anacetrapib lipid modifying therapy in patients with heterozygous familial hypercholesterolemia realize study
    Circulation, 2014
    Co-Authors: John J P Kastelein, Sukrut Shah, Joost Besseling, Jean Bergeron, G Langslet, Kees G Hovingh, Naab Alsaady, Michiel Koeijvoets, John Hunter, Amy O Johnsonlevonas
    Abstract:

    Introduction: Anacetrapib, a cholesteryl ester transfer protein inhibitor, has been shown to robustly reduce atherogenic lipoproteins including low-density lipoprotein cholesterol (LDL-C), Apo B and raise high-density lipoprotein cholesterol (HDL-C) as well as ApoA1. Hypothesis: This 1-year, Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy and safety profile of Anacetrapib added to optimized LDL-C lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH). Methods: Patients with a genotype-confirmed or clinical diagnosis of HeFH, treated with an optimal dose of statin ± other lipid-modifying medication(s) and having an LDL-C ≥100 mg/dL without history of cardiovascular disease or LDL-C ≥70 mg/dL with a history of CVD were randomized in a ratio of 2:1 to Anacetrapib 100 mg (n=204) or placebo (n=102) for 52 weeks followed by a 12-week reversal phase. The primary end points were the percent change from baseline in LDL-C (beta-quantification method) and the safety profile of Anacetrapib. This trial is registered in ClinicalTrials.gov, #NCT01524289. Results: A total of 306 patients were enrolled at 25 sites in 9 countries. At baseline, most patients were on high-dose statin therapy and >70% also were on ezetimibe. Baseline LDL-C and HDL-C were 129.4 and 53.3 mg/dL, respectively. At Week 52, Anacetrapib vs. placebo significantly reduced LDL-C by 39.7% and increased HDL-C by 102.1% (p Conclusion: In patients with HeFH, treatment with Anacetrapib for 1 year was generally well tolerated and resulted in substantial reductions in LDL-C and increases in HDL-C.