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Tolerability, pharmacokinetics and pharmacodynamics of TA ‐8995, a selective cholesteryl ester transfer protein ( CETP ) inhibitor, in healthy subjects
Author(s) -
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.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12380
Subject(s) - tolerability , pharmacokinetics , cholesterylester transfer protein , pharmacodynamics , placebo , medicine , apolipoprotein b , pharmacology , adverse effect , urine , dosing , endocrinology , cholesterol , lipoprotein , alternative medicine , pathology
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 ( C aucasian males, 18–55 years), 25 mg ( C aucasian males, > 65 years and C aucasian females, 18–55 years), 25, 50, 100 and 150 mg ( J apanese males, 18–55 years). Study 2: C aucasian 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.