Document Detail

A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat.
MedLine Citation:
PMID:  22616739     Owner:  NLM     Status:  MEDLINE    
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) concentratios 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 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ(1-40) serum concentrations showed a pattern of decreasing concentrations over the first 4-6 h 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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  75     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-08-05     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  136-45     Citation Subset:  IM    
Copyright Information:
© 2012 Bristol-Myers Squibb. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Administration, Oral
Aged, 80 and over
Alzheimer Disease / drug therapy
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Double-Blind Method
Middle Aged
Oxadiazoles / adverse effects*,  pharmacokinetics,  pharmacology
Sulfonamides / adverse effects*,  pharmacokinetics,  pharmacology
Reg. No./Substance:
0/BMS 708163; 0/Oxadiazoles; 0/Sulfonamides; EC 3.4.-/Amyloid Precursor Protein Secretases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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