title: A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat.
abstract: OBJECTIVE
  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.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Hopewell, NJ, USA. gary.tong@bms.com
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Sverdlov
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.forename: Randy
authors.initials: R
authors.lastname: Slemmon
authors.forename: Robert
authors.initials: R
authors.lastname: Croop
authors.forename: Lorna
authors.initials: L
authors.lastname: Castaneda
authors.forename: Huidong
authors.initials: H
authors.lastname: Gu
authors.forename: Oi
authors.initials: O
authors.lastname: Wong
authors.forename: Hewei
authors.initials: H
authors.lastname: Li
authors.forename: Robert M
authors.initials: RM
authors.lastname: Berman
authors.forename: Christina
authors.initials: C
authors.lastname: Smith
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Randy
authors.initials: R
authors.lastname: Dockens
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C554092:BMS 708163; D010069:Oxadiazoles; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases