Pharmacokinetic, pharmacodynamic, and safety profile of a new cholesteryl ester transfer protein inhibitor in healthy human subjects.
A new cholesteryl ester (CE) transfer protein (CETP) inhibitor (CP-800,569) was evaluated. Doses of 30-1,800 mg were administered once daily to healthy subjects for 14 days. Serum CP-800,569 levels increased, and CETP activity decreased, in a dose-related manner. Serum levels of high-density lipoprotein (HDL) increased (by a maximum of 156%), and those of low-density lipoprotein (LDL) decreased (by a maximum of 47%). CP-800,569 also had the effect of lowering postprandial triglyceride levels. Trough concentrations of apolipoprotein E (apoE) increased: the maximum increases were 89% for total plasma apoE and 280% for HDL apoE. By contrast, the postprandial increases in total plasma levels of apoE and non HDL apoE were either diminished by CP-800,569 or reversed to decreases. CP-800,569 was very well tolerated, with some nonserious gastrointestinal adverse events seen only with the 1,800-mg dose. No changes in blood pressure (BP) were observed. The possible effects of higher CP-800,569 doses on aldosterone and cortisol levels could not be excluded. The results of this study may be useful in CP-800,569 dose selection.
Wolk
R
R
Global Research & Development, Pfizer, New London, Connecticut, USA. Robert.Wolk@pfizer.com
Chen
D
D
Clark
R W
RW
Mancuso
J
J
Barclay
P L
PL
D000293:Adolescent; D000328:Adult; D001057:Apolipoproteins E / Q000097:blood; D019540:Area Under Curve; D001555:Benzene Derivatives / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
D001057:Apolipoproteins E; D001555:Benzene Derivatives; C544112:CP-800,569; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006846:Hydrocarbons, Halogenated; D014280:Triglycerides