ABSTRACT: 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.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.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.TA-8995 is a potent CETP inhibitor and warrants further investigation.