title: Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.
abstract: OBJECTIVE
  Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.
  
  
  METHODS
  Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21-28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests.
  
  
  RESULTS
  Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated.
  
  
  CONCLUSIONS
  TA-8995 is a potent CETP inhibitor and warrants further investigation.
authors.affiliation: Dezima Pharma BV, Naarden, The Netherlands; Xention Ltd, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Ford
authors.forename: Matt
authors.initials: M
authors.lastname: Lawson
authors.forename: David
authors.initials: D
authors.lastname: Fowler
authors.forename: Nobuko
authors.initials: N
authors.lastname: Maruyama
authors.forename: Seiji
authors.initials: S
authors.lastname: Mito
authors.forename: Koichi
authors.initials: K
authors.lastname: Tomiyasu
authors.forename: Shuji
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Chisa
authors.initials: C
authors.lastname: Suzuki
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kawaguchi
authors.forename: Patrick
authors.initials: P
authors.lastname: Round
authors.forename: Malcolm
authors.initials: M
authors.lastname: Boyce
authors.forename: Steve
authors.initials: S
authors.lastname: Warrington
authors.forename: Werner
authors.initials: W
authors.lastname: Weber
authors.forename: Sander
authors.initials: S
authors.lastname: van Deventer
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D044465:White People; D055815:Young Adult
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011804:Quinolines; C000597751:TA-8995
keywords: apolipoproteins; cardiovascular diseases; cholesterol; coronary disease; hypercholesterolaemia