Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure.
ILLUMINATE, the phase 3 morbidity and mortality trial of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, plus atorvastatin terminated in 2006. The underlying morbidity and mortality cause remains undetermined. In addition to lipoprotein changes, off-target increases in blood pressure (BP), sodium, bicarbonate, and aldosterone and potassium decreases were described. We report nonclinical and clinical studies using torcetrapib and a closely related CETP inhibitor, CP-532,623, to further characterize this pharmacology. Pressor effects of torcetrapib and CP-532,623 were observed in monkeys and human subjects. CETP inhibition and high-density lipoprotein cholesterol elevation were demonstrated. In humans, high- versus low-dose CP-532,623 produced significantly greater pressor effects despite similar maximal CETP inhibition. Inhibition of CETP was seen 48 hours post dose, whereas BP elevation dissipated by 24 hours, temporally dissociating CETP inhibition from BP changes. These data, and structural similarities between the compounds, support the conclusion that the BP effects are related to chemotype. We also observed an acute aldosterone increase without changes in renin in monkeys. Continuous BP measurements showed persistent elevations, whereas aldosterone changes were transient, suggesting that increases in BP were not directly the result of renin-angiotensin-aldosterone system activation and may, in part, be due to direct effects on blood vessels or other nongenomic effects.
Blasi
Eileen
E
La Jolla Laboratories, Pfizer Global Research & Development, La Jolla, CA 92121, USA. eileen.r.blasi@pfizer.com
Bamberger
Mark
M
Knight
Delvin
D
Engwall
Mike
M
Wolk
Robert
R
Winter
Steven
S
Betts
Allison
A
John-Baptiste
Annette
A
Keiser
Joan
J
D000293:Adolescent; D000328:Adult; D000450:Aldosterone / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000924:Anticholesteremic Agents; C544076:CP 532,623; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D011804:Quinolines; D000450:Aldosterone; C483909:torcetrapib