Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Kumar, Sanjeev; Tan, Eugene; Hartmann, Georgy; Biddle, Zachary; Bergman, Arthur; Dru, James; Ho, Joanne; Jones, Allen N.; Staskiewicz, Steve J.; Braun, Matthew P.; Karanam, Bindhu V.; Dean, Dennis C.; Gendrano, Isaias Noel; Graves, Mark W.; Wagner, John A.; Krishna, Rajesh

doi:10.1124/dmd.109.028704

Cited by 34 publications

(33 citation statements)

References 8 publications

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“…As discussed in the companion article on the metabolism of anacetrapib in humans (Kumar et al, 2010), the only metabolites detected in biological matrices (plasma and feces) from healthy human volunteers given a single 150-mg oral dose of [ 14 C]anacetrapib were M1, M2, and M3. All of these metabolites were present at much lower levels than those of the parent in human plasma (Ͻ14% of total plasma, radioactivity).…”

Section: Downloaded Frommentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Tan

Hartmann²,

Chen³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics and metabolism of anacetrapib (MK-0859), a novel cholesteryl ester transfer protein inhibitor, were examined in rats and rhesus monkeys. Anacetrapib exhibited a low clearance in both species and a moderate oral bioavailability of ϳ38% in rats and ϳ13% in monkeys. The area under the plasma concentrationtime curve in both species increased in a less than dose-proportional manner over an oral dose range of 1 to 500 mg/kg. After oral administration of [ 14 C]anacetrapib at 10 mg/kg, ϳ80 and 90% of the radioactive dose was recovered over 48 h postdose from rats and monkeys, respectively. The majority of the administered radioactive dose was excreted unchanged in feces in both species. Biliary excretion of radioactivity accounted for ϳ15% and urinary excretion for less than 2% of the dose. Thirteen metabolites, resulting from oxidative and secondary glucuronic acid conjugation, were identified in rat and monkey bile. The main metabolic pathways consisted of O-demethylation (M1) and hydroxylation on the biphenyl moiety (M2) and hydroxylation on the isopropyl side chain (M3); these hydroxylations were followed by O-glucuronidation of these metabolites. A glutathione adduct (M9), an olefin metabolite (M10), and a propionic acid metabolite (M11) also were identified. In addition to parent anacetrapib, M1, M2, and M3 metabolites were detected in rat but not in monkey plasma. Overall, it appears that anacetrapib exhibits a low-to-moderate degree of absorption after oral dosing and majority of the absorbed dose is eliminated via oxidation to a series of hydroxylated metabolites that undergo conjugation with glucuronic acid before excretion into bile.A significant amount of effort is being put into developing therapeutic agents that are capable of lowering low-density lipoprotein (LDL) levels because increased circulating levels of LDL have been demonstrated to increase risk for cardiovascular disease and associated clinical sequelae (Kannel et al., 1979;Castelli et al., 1983;Stamler et al., 1988). Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) remain the cornerstone of LDL-lowering therapy and have been demonstrated to reduce cardiovascular risk in humans (Shepherd et al., 1995). However, there remains a high incidence of residual cardiovascular events even after aggressive treatment with LDL-lowering drugs (Bays and Stein, 2003). It has recently been shown that, in addition to LDL, high-density lipoprotein (HDL) cholesterol is an independent factor that may modulate the risk of cardiovascular disease. Epidemiological evidence suggests that plasma HDL cholesterol levels are inversely correlated with atherosclerosis and cardiovascular risk (Asztalos et al., 2004;Cobain et al., 2007). However, there are no clinical outcome data to support this hypothesis at the present time. One class of dyslipidemia agents that affect HDL cholesterol levels are the inhibitors of cholesteryl ester transfer protein (CETP) (Hesler et al., 1987;Linsel-Nitschke and Tall, 2005). CETP is a plasma glycop...

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Section: Downloaded Frommentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Tan

Hartmann²,

Chen³

et al. 2009

Drug Metab Dispos

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“…The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A [37,38].…”

Section: Drug Interaction Studies Of Anacetrapibmentioning

confidence: 98%

Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update

Ghosh

Ghosh²

2012

CCP

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Introduction: The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP).Areas Covered: Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels.In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

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“…The pharmacokinetics of anacetrapib have been evaluated in healthy humans, dyslipidemic subjects, and animal models 25,42–45. Following a 1-hour delay, anacetrapib is promptly absorbed with peak concentrations arising approximately 4 hours after administration 25,43–45.…”

Section: Pharmacokinetics Drug Interactions and Pharmacodynamicsmentioning

confidence: 99%

“…Following a 1-hour delay, anacetrapib is promptly absorbed with peak concentrations arising approximately 4 hours after administration 25,43–45. Although anacetrapib is highly plasma protein-bound, the binding is reversible.…”

Section: Pharmacokinetics Drug Interactions and Pharmacodynamicsmentioning

confidence: 99%

Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib

Miyares

Davis²

2012

VHRM

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Cardiovascular disease (CVD) is responsible for significant morbidity and mortality within the United States and worldwide. Although targeting low-density lipoprotein cholesterol (LDL-C) in the prevention of CVD has been shown to be effective, evidence exists to indicate that significant cardiovascular (CV) risk remains in patients receiving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) – a risk that may be correlated with low levels of high-density lipoprotein cholesterol (HDL-C). Among the various tactics under investigation to increase HDL-C, inhibition of cholesteryl ester transfer protein (CETP) appears the most adept to raise these levels. Although torcetrapib, a CETP inhibitor, demonstrated significant beneficial changes in HDL-C and LDL-C after 12 months of therapy when coadministered with atorvastatin, patients in the torcetrapib arm experienced a rise in mortality, including increased risk of death from CV and non-CV causes as well as a significant rise in major CV events. Later studies established that the adverse effects of torcetrapib were produced from molecule-specific off-target effects and not to the mechanism of CETP inhibition. These untoward outcomes have not been detected with anacetrapib, the third of the CETP inhibitors to enter Phase III trials. Furthermore, treatment with anacetrapib revealed both a statistically significant decrease in LDL-C and increase in HDL-C over placebo. While the place in therapy of niacin and fibrates to reduce CV events is currently in question secondary to the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes and the Action to Control CV Risk in Diabetes trials, the ongoing large-scale, randomized–placebo, controlled-outcomes study with anacetrapib coadministered with statin treatment will not only test the hypothesis if CETP inhibition lowers residual CV risk but will also provide insight as to which patient subgroups might benefit the most from anacetrapib despite aggressive therapy with statins.

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Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Cited by 34 publications

References 8 publications

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update

Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib

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