title: Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease.
abstract: The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.
authors.affiliation: Office of the Vice President, Weill Cornell Medical College, New York, New York. Electronic address: amg2004@med.cornell.edu.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gotto
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Xiujiang Susie
authors.initials: XS
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Sanskruti
authors.initials: S
authors.lastname: Vaidya
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Uma
authors.initials: U
authors.lastname: Kher
authors.affiliation: Utah Foundation for Biomedical Research and Utah Lipid Center, Salt Lake City, Utah.
authors.forename: Eliot A
authors.initials: EA
authors.lastname: Brinton
authors.affiliation: Radiant Research, Chicago, Illinois.
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
authors.affiliation: Office of the Vice President, Weill Cornell Medical College, New York, New York.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Moon
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Sukrut
authors.initials: S
authors.lastname: Shah
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Hayes M
authors.initials: HM
authors.lastname: Dansky
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Yale
authors.initials: Y
authors.lastname: Mitchel
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Barter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D053480:Cholesterol Ester Transfer Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D003327:Coronary Disease / Q000097:blood* / Q000453:epidemiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012189:Retrospective Studies; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008055:Lipids; D023303:Oxazolidinones; C530884:anacetrapib