Tolerability, pharmacokinetics and pharmacodynamics of TA‐8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 78; no. 3; pp. 498 - 508
• Main Authors: Ford, John, Lawson, Matt, Fowler, David, Maruyama, Nobuko, Mito, Seiji, Tomiyasu, Koichi, Kinoshita, Shuji, Suzuki, Chisa, Kawaguchi, Atsuhiro, Round, Patrick, Boyce, Malcolm, Warrington, Steve, Weber, Werner, Deventer, Sander, Kastelein, John J. P.
• Format: Journal Article
• Language: English
• Published: England BlackWell Publishing Ltd 01.09.2014
• Subjects: Adolescent; Adult; apolipoproteins; Asian Continental Ancestry Group; cardiovascular diseases; cholesterol; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol, HDL - blood; Cholesterol, LDL - blood; coronary disease; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; European Continental Ancestry Group; Female; Half-Life; Humans; hypercholesterolaemia; Male; Middle Aged; Pharmacodynamics; Quinolines - administration & dosage; Quinolines - pharmacokinetics; Quinolines - pharmacology; Young Adult; coronary disease; cholesterol; apolipoproteins; cardiovascular diseases; hypercholesterolaemia
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12380

Aims 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.