title: Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study.
abstract: Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.
authors.affiliation: Office of the Vice President, Weill Cornell Medical College, New York, NY, USA amg2004@med.cornell.edu.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gotto
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Kher
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Manash Shankar
authors.initials: MS
authors.lastname: Chatterjee
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Xiujiang Susie
authors.initials: XS
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Sanskruti
authors.initials: S
authors.lastname: Vaidya
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Utah Foundation for Biomedical Research and Utah Lipid Center, Salt Lake City, UT, USA.
authors.forename: Eliot A
authors.initials: EA
authors.lastname: Brinton
authors.affiliation: Office of the Vice President, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Moon
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Sukrut
authors.initials: S
authors.lastname: Shah
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Hayes M
authors.initials: HM
authors.lastname: Dansky
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Yale
authors.initials: Y
authors.lastname: Mitchel
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Barter
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D023303:Oxazolidinones; C530884:anacetrapib
keywords: anacetrapib; lipids; long-term safety; plasma concentrations