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Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY 3000328, in healthy subjects
Author(s) -
Payne Christopher D.,
Deeg Mark A.,
Chan Melanie,
Tan Lai Hock,
LaBell Elizabeth Smith,
Shen Tong,
DeBrota David J.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12470
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , tolerability , medicine , placebo , clearance , adverse effect , urology , pathology , alternative medicine
Aim The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY 3000328 when administered as single escalating doses to healthy volunteers. Methods This was a phase 1, placebo‐controlled, dose escalation study with LY 3000328 in 21 healthy male volunteers. Subjects were administered escalating LY 3000328 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 LY 3000328 pharmacokinetics and the measurement of cathepsin S ( C at S ) activity, C at S mass and calculated C at S specific activity. Results All doses of LY 3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY 3000328 was measured ex vivo showing a biphasic response to LY 3000328, where C at S activity declines, then returns to baseline, and then increases to a level above baseline. C at S mass was also assessed post‐dose which increased in a dose‐dependent manner, and continued to increase after LY 3000328 had been cleared from the body. C at S specific activity was additionally calculated to normalize C at S activity for changes in C at S mass. This demonstrated the increase in C at S activity was attributable to the increase in C at S mass detected in plasma. Conclusion A specific inhibitor of C at S which is cleared quickly from plasma may produce a transient decrease in plasma C at S activity which is followed by a more prolonged increase in plasma C at S mass which may have implications for the future clinical development of inhibitors of Cat S .