title: Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.
abstract: OBJECTIVE
  The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers.
  
  
  METHODS
  This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity.
  
  
  RESULTS
  All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma.
  
  
  CONCLUSIONS
  A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Payne
authors.forename: Mark A
authors.initials: MA
authors.lastname: Deeg
authors.forename: Melanie
authors.initials: M
authors.lastname: Chan
authors.forename: Lai Hock
authors.initials: LH
authors.lastname: Tan
authors.forename: Elizabeth Smith
authors.initials: ES
authors.lastname: LaBell
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.forename: David J
authors.initials: DJ
authors.lastname: DeBrota
mesh_terms: D000328:Adult; D001578:Benzopyrans / Q000493:pharmacokinetics* / Q000494:pharmacology; D002219:Carbamates / Q000493:pharmacokinetics* / Q000494:pharmacology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000493:pharmacokinetics*
chemical_list: D001578:Benzopyrans; D002219:Carbamates; C000601502:LY3000328; D011480:Protease Inhibitors; D002403:Cathepsins; C028217:cathepsin S
keywords: LY3000328; cathepsin S inhibitor