The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Rajesh Krishna - One of the best experts on this subject based on the ideXlab platform.
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anacetrapib a novel CETP Inhibitor pursuing a new approach to cardiovascular risk reduction
Clinical Pharmacology & Therapeutics, 2012Co-Authors: David E Gutstein, Yale B Mitchel, Rajesh Krishna, Douglas G Johns, Howard K Surks, Hayes M Dansky, Sonia Shah, J Arena, John A WagnerAbstract:Cholesteryl ester transfer protein (CETP) inhibition is a promising experimental strategy to raise high-density lipoprotein cholesterol (HDL-C) and reduce cardiovascular risk. This review focuses on the highly selective and potent CE TP Inhibitor anacetrapib and discusses the available preclinical and clinical information pertaining to it. We also describe strategies to target HDL-C, discuss the mechanism underlying CETP inhibition and its effects on lipid biology, and give an overview of other CETP Inhibitors that are currently in development.
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single dose pharmacokinetics and pharmacodynamics of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy subjects
British Journal of Clinical Pharmacology, 2009Co-Authors: Rajesh Krishna, Amit Garg, Arthur J Bergman, Josee Cote, P Van Hoydonck, T Laethem, K Van Dyck, Deborah Panebianco, Jingjing Chen, Cynthia ChavezengAbstract:AIMS: Anacetrapib is an orally active and potent Inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
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assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy subjects
British Journal of Clinical Pharmacology, 2009Co-Authors: Rajesh Krishna, Amit Garg, Sara Sadeghi Keshavarz, Frederick A Bieberdorf, Jeffrey A Chodakewitz, John A WagnerAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for the treatment of dyslipidaemia, for which hydroxy-3-methylglutaryl coenzyme A reductase Inhibitors remain a cornerstone of therapy. • Clinical studies published to date with other investigational CETP Inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), have been evaluated in the presence of statins, but it remains unclear whether there is a clinically meaningful interaction between a CETP Inhibitor and a statin, and whether the low-density lipoprotein-cholesterol (LDL-C)-lowering effects are additive with the combination. WHAT THIS STUDY ADDS • This is the first study to show that there is no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. • When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C- and apolipoprotein (Apo) B-lowering efficacy, due to CETP inhibition, the magnitude of which appears greater than any combination of CETP Inhibitor and statin evaluated to date. • The study also provides useful insights into the LDL-C- and Apo B-lowering effects when a CETP Inhibitor is given in combination with a statin. AIMS Anacetrapib is an orally active, potent Inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase Inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. METHODS A randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. RESULTS Both treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC0–24 h geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of −36% (−27, −46) compared with a reduction of −54% (−44, −63) for anacetrapib co-administered with simvastatin. CONCLUSIONS There appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated.
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assessment of the cyp3a mediated drug interaction potential of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy volunteers
The Journal of Clinical Pharmacology, 2009Co-Authors: Rajesh Krishna, Amit Garg, Arthur J Bergman, Josee Cote, T Laethem, Brad Roadcap, Rita Chiou, Regina W Wang, Varsha Didolkar, Eva VetsAbstract:: In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-Inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein Inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
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multiple dose pharmacodynamics and pharmacokinetics of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy subjects
Clinical Pharmacology & Therapeutics, 2008Co-Authors: Rajesh Krishna, Arthur J Bergman, M Fallon, Josee Cote, P Van Hoydonck, T Laethem, I N Gendrano, K Van Dyck, Deborah Hilliard, Omar F LaterzaAbstract:Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the heteroexchange of cholesteryl esters from high-density lipoprotein (HDL) and triglycerides to apolipoprotein B–containing lipoproteins, especially very low–density lipoproteins (LDL-C).1,2 Clinical Pharmacology & Therapeutics (2008); 84, 6, 679–683 doi:10.1038/clpt.2008.109
Stephen J Nicholls - One of the best experts on this subject based on the ideXlab platform.
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Clinical trials with cholesteryl ester transfer protein Inhibitors.
Current Opinion in Lipidology, 2016Co-Authors: Belinda A. Di Bartolo, My Ngan Duong, Stephen J NichollsAbstract:PURPOSE OF REVIEW: Inhibition of cholesteryl ester transfer protein (CETP) has received considerable interest by virtue of its favorable effects on atherogenic and protective lipid parameters. The impact of CETP Inhibitors in large clinical outcome trials will be reviewed. RECENT FINDINGS: Population and genetic studies demonstrate that low CETP activity associates with lower rates of cardiovascular events. Inhibiting CETP activity in animal models has a favorable impact on experimental atherosclerosis. Although the first CETP Inhibitor to advance to an outcome trial proved to have adverse clinical effects and the next agent, a more modest Inhibitor, was clinically futile, there continues to be immense interest in the potential to develop nontoxic, potent CETP Inhibitors to reduce cardiovascular risk. SUMMARY: The current status of CETP Inhibitors in the context of large outcomes trials will be reviewed.
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CETP Inhibition in CVD Prevention: an Actual Appraisal.
Current Cardiology Reports, 2016Co-Authors: Belinda A. Di Bartolo, Kohei Takata, My Ngan Duong, Stephen J NichollsAbstract:By virtue of their effects on low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and cellular cholesterol efflux, there is considerable interest in the potential use of pharmacological Inhibitors of cholesteryl ester transfer protein (CETP) as a novel approach for cardiovascular disease prevention. This is supported by observations from genetic and animal studies suggesting that less CETP activity has favorable cardiovascular effects. Despite the adverse effects of the first CETP Inhibitor to move forward in clinical development, torcetrapib, there remains considerable interest in developing alternative CETP Inhibitors without the off-target effects of torcetrapib. The clinical development programs leading to a number of promising CETP Inhibitors will be reviewed.
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cyp mediated drug drug interactions with evacetrapib an investigational CETP Inhibitor in vitro prediction and clinical outcome
British Journal of Clinical Pharmacology, 2015Co-Authors: Ellen A Cannady, Jeffrey G Suico, Ming Dauh Wang, Stuart Friedrich, Jessica Rehmel, Stephen J Nicholls, Kathryn A KruegerAbstract:Aims Evacetrapib is a cholesteryl ester transfer protein (CETP) Inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP Inhibitors are likely to be utilized as ‘add-on’ therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug–drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated. Methods The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic. Results In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki) ranging from 0.57 µm (CYP2C9) to 7.6 µm (CYP2C19). Evacetrapib was a time-dependent Inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co-administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady-state, with no differences in reported hepatic or muscular adverse events. Conclusions Taken together, the extent of CYP-mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.
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Evacetrapib
Current Cardiology Reports, 2012Co-Authors: Stephen J NichollsAbstract:Considerable attention focuses on the ability to develop therapeutic agents that elevate levels of high-density lipoprotein cholesterol (HDL-C). Cholesteryl ester transfer protein (CETP) Inhibitors have been developed on the basis of their ability to raise HDL-C to a greater extent than lipid-modifying therapies currently used in clinical practice. Initial enthusiasm for CETP inhibition decreased as a result of adverse clinical outcomes observed with the agent torcetrapib. Elucidating off-target toxicities of torcetrapib has provided hope that other CETP Inhibitors may still be of potential benefit. Evacetrapib is a novel CETP Inhibitor, with favorable effects on plasma lipids and no adverse effects on blood pressure or mineralocorticoid activity in early clinical evaluation. The potential effects on cardiovascular outcomes remain to be determined.
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effects of the CETP Inhibitor evacetrapib administered as monotherapy or in combination with statins on hdl and ldl cholesterol a randomized controlled trial
JAMA, 2011Co-Authors: Stephen J Nicholls, Ming Dauh Wang, Kathryn A Krueger, John J.p. Kastelein, Bryan H Brewer, Mingyuan Shao, Bo Hu, Ellen Mcerlean, Steven E NissenAbstract:Context Interest remains high in cholesteryl ester transfer protein (CETP) Inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP Inhibitors in combination with commonly used statins. Objective To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia. Design, Setting, and Participants Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe. Interventions Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks. Main Outcome Measures The co–primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment. Results The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of −0.7 mg/dL (−3.0%; P Conclusions Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation. Trial Registration clinicaltrials.gov Identifier: NCT01105975
Josee Cote - One of the best experts on this subject based on the ideXlab platform.
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effects of rifampin a potent inducer of drug metabolizing enzymes and an Inhibitor of oatp1b1 3 transport on the single dose pharmacokinetics of anacetrapib
The Journal of Clinical Pharmacology, 2013Co-Authors: Matt S Anderson, Amy O Johnsonlevonas, Josee Cote, Daria Stypinski, Patrice Auger, Anne Hohnstein, Scott Rasmussen, David E GutsteinAbstract:: Anacetrapib is a novel cholesteryl ester transfer protein (CETP) Inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
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single dose pharmacokinetics and pharmacodynamics of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy subjects
British Journal of Clinical Pharmacology, 2009Co-Authors: Rajesh Krishna, Amit Garg, Arthur J Bergman, Josee Cote, P Van Hoydonck, T Laethem, K Van Dyck, Deborah Panebianco, Jingjing Chen, Cynthia ChavezengAbstract:AIMS: Anacetrapib is an orally active and potent Inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
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assessment of the cyp3a mediated drug interaction potential of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy volunteers
The Journal of Clinical Pharmacology, 2009Co-Authors: Rajesh Krishna, Amit Garg, Arthur J Bergman, Josee Cote, T Laethem, Brad Roadcap, Rita Chiou, Regina W Wang, Varsha Didolkar, Eva VetsAbstract:: In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-Inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein Inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
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multiple dose pharmacodynamics and pharmacokinetics of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy subjects
Clinical Pharmacology & Therapeutics, 2008Co-Authors: Rajesh Krishna, Arthur J Bergman, M Fallon, Josee Cote, P Van Hoydonck, T Laethem, I N Gendrano, K Van Dyck, Deborah Hilliard, Omar F LaterzaAbstract:Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the heteroexchange of cholesteryl esters from high-density lipoprotein (HDL) and triglycerides to apolipoprotein B–containing lipoproteins, especially very low–density lipoproteins (LDL-C).1,2 Clinical Pharmacology & Therapeutics (2008); 84, 6, 679–683 doi:10.1038/clpt.2008.109
Cynthia Chavezeng - One of the best experts on this subject based on the ideXlab platform.
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single dose pharmacokinetics and pharmacodynamics of anacetrapib a potent cholesteryl ester transfer protein CETP Inhibitor in healthy subjects
British Journal of Clinical Pharmacology, 2009Co-Authors: Rajesh Krishna, Amit Garg, Arthur J Bergman, Josee Cote, P Van Hoydonck, T Laethem, K Van Dyck, Deborah Panebianco, Jingjing Chen, Cynthia ChavezengAbstract:AIMS: Anacetrapib is an orally active and potent Inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
David E Gutstein - One of the best experts on this subject based on the ideXlab platform.
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effects of rifampin a potent inducer of drug metabolizing enzymes and an Inhibitor of oatp1b1 3 transport on the single dose pharmacokinetics of anacetrapib
The Journal of Clinical Pharmacology, 2013Co-Authors: Matt S Anderson, Amy O Johnsonlevonas, Josee Cote, Daria Stypinski, Patrice Auger, Anne Hohnstein, Scott Rasmussen, David E GutsteinAbstract:: Anacetrapib is a novel cholesteryl ester transfer protein (CETP) Inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-∞ and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-∞ and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
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anacetrapib a novel CETP Inhibitor pursuing a new approach to cardiovascular risk reduction
Clinical Pharmacology & Therapeutics, 2012Co-Authors: David E Gutstein, Yale B Mitchel, Rajesh Krishna, Douglas G Johns, Howard K Surks, Hayes M Dansky, Sonia Shah, J Arena, John A WagnerAbstract: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.