| A contrast in safety, pharmacokinetics, and pharmacodynamics across age groups after a single 50-mg oral dose of the γ-secretase inhibitor avagacestat. | |
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MedLine Citation:
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PMID: 22616739 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Aim: To evaluate the single-dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women. Methods: All subjects received double-blinded administration of a single 50-mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)(1-40) levels, and exploration of Notch biomarkers. Results: Avagacestat 50-mg capsule was well-tolerated and rapidly absorbed among young and elderly subjects, with a median T(max) between 1 and 2 hours post-dose and an average half-life between 41 and 71 hours. In general, subjects aged 75 years or more had higher AUC(inf) values than those aged less than 75 years. An exploratory analysis of Aβ(1-40) serum levels showed a pattern of decreasing levels over the first 4-6 hours followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose-limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly. Conclusions: The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease © 2012 Bristol-Myers Squibb. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society. |
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Authors:
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Gary Tong; Jun-Sheng Wang; Oleksandr Sverdlov; Shu-Pang Huang; Randy Slemmon; Robert Croop; Lorna Castaneda; Huidong Gu; Oi Wong; Hewei Li; Robert M Berman; Christina Smith; Charles F Albright; Randy Dockens |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-5-23 |
Journal Detail:
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Title: British journal of clinical pharmacology Volume: - ISSN: 1365-2125 ISO Abbreviation: - Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-5-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7503323 Medline TA: Br J Clin Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 Bristol-Myers Squibb. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society. |
Affiliation:
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Research and Development, Bristol-Myers Squibb, Hopewell, NJ, Research and Development, Bristol-Myers Squibb, Lawrenceville, NJ, Research and Development, Bristol-Myers Squibb, Wallingford, CT. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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