on January 22, 2004
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
Published online before print January 22, 2004, doi: 10.1161/01.ATV.0000118278.21719.17
Published online before print January 22, 2004, doi: 10.1161/01.ATV.0000118278.21719.17
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Submitted on November 3, 2003
Accepted on January 12, 2004
Raising High-Density Lipoprotein in Humans Through Inhibition of Cholesteryl Ester Transfer Protein: An Initial Multidose Study of Torcetrapib
Ronald W. Clark *;
From the Departments of Cardiovascular and Metabolic Diseases (R.W.C., R.B.R., E.D.S., G.M.-A., P.G.C., T.M.S., R.T.W., M.J.B.), Clinical Sciences (T.A.S.), Pharmacokinetics Dynamics and Metabolism (A.T.W.), Pharmaceutical Research (M.E.P.), and Materials Management (J.A.W.), Pfizer Global Research and Development, Groton, Conn.
* To whom correspondence should be addressed. E-mail: ronald_w_clark{at}groton.pfizer.com.
Objective-- The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib (CP-529,414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study.
Methods and Results-- Five groups of 8 subjects each were randomized to placebo (n=2) or torcetrapib (n=6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study. The correlation of plasma drug levels with inhibition (EC50=43 nM) was as expected based on in vitro potency (IC50 
50 nM), and increases in CETP mass were consistent with the proposed mechanism of inhibition. CETP inhibition increased with escalating dose, leading to elevations of HDL-C of 16% to 91%. Total plasma cholesterol did not change significantly because of a reduction in nonHDL-C, including a 21% to 42% lowering of low-density lipoprotein cholesterol at the higher doses. Apolipoprotein A-I and E were elevated 27% and 66%, respectively, and apoB was reduced 26% with 120 mg twice daily. Cholesteryl ester content decreased and triglyceride increased in the nonHDL plasma fraction, with contrasting changes occurring in HDL.
Conclusions-- These effects of CETP inhibition resemble those observed in partial CETP deficiency. This work serves as a prelude to further studies in subjects with low HDL, or combinations of dyslipidemia, in assessing the role of CETP in atherosclerosis.
Key words: CETP • HDL • torcetrapib • CP-529,414 • atherosclerosis
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|
|
|
|
|
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|
|
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|
|
|
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|
|
|
|
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|
|
|
|
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|
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|
|
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 S. H Wild and C. D Byrne Review: Treatment of lipids to reduce cardiovascular risk among people with the metabolic syndrome or type 2 diabetes The British Journal of Diabetes & Vascular Disease, November 1, 2005; 5(6): 315 - 319. [Abstract] [PDF]
|
|
|
|
|
|
A. M. Gotto Jr Evolving Concepts of Dyslipidemia, Atherosclerosis, and Cardiovascular Disease: The Louis F. Bishop Lecture J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1219 - 1224. [Full Text] [PDF]
|
|
|
|
|
|
A. Gauthier, P. Lau, X. Zha, R. Milne, and R. McPherson Cholesteryl Ester Transfer Protein Directly Mediates Selective Uptake of High Density Lipoprotein Cholesteryl Esters by the Liver Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2177 - 2184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Lewis and D. J. Rader New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport Circ. Res., June 24, 2005; 96(12): 1221 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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