Tolerability,pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor,in healthy subjects |
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Authors: | John Ford Matt Lawson David Fowler Nobuko Maruyama Seiji Mito Koichi Tomiyasu Shuji Kinoshita Chisa Suzuki Atsuhiro Kawaguchi Patrick Round Malcolm Boyce Steve Warrington Werner Weber Sander van Deventer John J P Kastelein |
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Institution: | 1.Dezima Pharma BV, Naarden, The Netherlands;2.Xention Ltd, Cambridge, UK;3.Mitsubishi Pharma Europe Limited, London, UK;4.Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan;5.Hammersmith Medicines Research, London, UK;6.MPS Hamburg GmbH, Hamburg, Germany;7.Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands;8.Department of Vascular Medicine, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands |
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Abstract: | AimsTwo 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.MethodsStudy 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.ResultsPeak 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.ConclusionsTA-8995 is a potent CETP inhibitor and warrants further investigation. |
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Keywords: | apolipoproteins cardiovascular diseases cholesterol coronary disease hypercholesterolaemia |
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