Effects of anacetrapib on plasma lipids, apolipoproteins and PCSK9 in healthy, lean rhesus macaques.
Inhibition of cholesteryl ester transfer protein (CETP) has been vigorously pursued as a potential therapy to treat patients who are at an elevated risk for coronary artery disease. Anacetrapib, a novel CETP inhibitor, has been shown clinically to raise HDL cholesterol and reduce LDL cholesterol when provided as monotherapy or when co-administered with a statin. Preclinically, the effects of anacetrapib on the functionality and composition of HDL have been extensively studied. In contrast, the effects of anacetrapib on other parameters related to lipoprotein metabolism and cardiovascular risk have been difficult to explore. The aim of the present investigation was to evaluate the effects of anacetrapib in rhesus macaques and to compare these to effects reported in dyslipidemic humans. Our results from two separate studies show that administration of anacetrapib (150 mg/kg q.d. for 10 days) to rhesus macaques results in alterations in CETP activity (reduced by more than 70%) and HDL cholesterol (increased by more than 110%) which are similar to those reported in dyslipidemic humans. Levels of LDL cholesterol were reduced by more than 60%, an effect slightly greater than what has been observed clinically. Treatment with anacetrapib in this model was also found to lead to statistically significant reductions in plasma PCSK9 and to reduce cholesterol excursion in the combined chylomicron and remnant lipoprotein fraction isolated from plasma by fast protein liquid chromatography. Collectively, these data suggest that rhesus macaques may be a useful translational model to study the mechanistic effects of CETP inhibition.
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Thomas P
TP
Roddy
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: david_mclaren@merck.com.
David G
DG
McLaren
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Ying
Y
Chen
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Dan
D
Xie
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Keiana
K
Dunn
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Alison
A
Kulick
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Daphne
D
Szeto
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Gail
G
Forrest
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Kelly
K
Albanese
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Marcie
M
Donnelly
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Cesaire
C
Gai
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Andrew
A
Gewain
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Harmony
H
Lederman
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Kristian K
KK
Jensen
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Xi
X
Ai
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Petr
P
Vachal
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Karen O
KO
Akinsanya
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Michele A
MA
Cleary
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Stephen F
SF
Previs
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Hayes M
HM
Dansky
Merck Research Laboratories, Merck & Co., Inc. 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Douglas G
DG
Johns
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001053:Apolipoproteins / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D008253:Macaca mulatta; D008297:Male; D023303:Oxazolidinones / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000097:blood; D012697:Serine Endopeptidases / Q000097:blood; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001053:Apolipoproteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D023303:Oxazolidinones; D014280:Triglycerides; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C530884:anacetrapib
Anacetrapib; Cholesteryl ester transfer protein; Lipoproteins; PCSK9; Rhesus macaques