Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.
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.


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 approximately 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.
Clark
Ronald W
RW
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Conn 06340, USA. ronald_w_clark@groton.pfizer.com
Sutfin
Tamara A
TA
Ruggeri
Roger B
RB
Willauer
Ann T
AT
Sugarman
Eliot D
ED
Magnus-Aryitey
George
G
Cosgrove
Patricia G
PG
Sand
Thomas M
TM
Wester
Ronald T
RT
Williams
John A
JA
Perlman
Michael E
ME
Bamberger
Mark J
MJ
D000293:Adolescent; D000328:Adult; D001053:Apolipoproteins / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*
D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D011804:Quinolines; C483909:torcetrapib