AIM: 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. CONCLUSION: 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.
RCT Entities:
AIM: 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. CONCLUSION: 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: Edward R Smith; Laurie A Tomlinson; Martin L Ford; Lawrence P McMahon; Chakravarthi Rajkumar; Stephen G Holt Journal: Hypertension Date: 2012-03-12 Impact factor: 10.190
Authors: Said Abisi; Kevin G Burnand; Matthew Waltham; Julia Humphries; Peter R Taylor; Alberto Smith Journal: J Vasc Surg Date: 2007-12 Impact factor: 4.268
Authors: Sofia Jormsjö; Dirk M Wuttge; Allan Sirsjö; Carl Whatling; Anders Hamsten; Sten Stemme; Per Eriksson Journal: Am J Pathol Date: 2002-09 Impact factor: 4.307
Authors: Prabhakar K Jadhav; Matthew A Schiffler; Kostas Gavardinas; Euibong J Kim; Donald P Matthews; Michael A Staszak; D Scott Coffey; Bruce W Shaw; Kenneth C Cassidy; Richard A Brier; Yuke Zhang; Robert M Christie; William F Matter; Keyun Qing; Jim D Durbin; Yong Wang; Gary G Deng Journal: ACS Med Chem Lett Date: 2014-08-27 Impact factor: 4.345
Authors: Catera L Wilder; Charlene Walton; Valencia Watson; Fermin A A Stewart; Jade Johnson; Shelly R Peyton; Christine K Payne; Valerie Odero-Marah; Manu O Platt Journal: Int J Biochem Cell Biol Date: 2016-08-31 Impact factor: 5.085
Authors: Kristina Oresic Bender; Leslie Ofori; Wouter A van der Linden; Elliot D Mock; Gopal K Datta; Somenath Chowdhury; Hao Li; Ehud Segal; Mateo Sanchez Lopez; Jonathan A Ellman; Carl G Figdor; Matthew Bogyo; Martijn Verdoes Journal: J Am Chem Soc Date: 2015-04-01 Impact factor: 15.419
Authors: Maria C Edman; Srikanth R Janga; Zhen Meng; Mercy Bechtold; Alexander F Chen; Chongiin Kim; Luke Naman; Arunava Sarma; Neha Teekappanavar; Alice Y Kim; Sara Madrigal; Simranjit Singh; Elizabeth Ortiz; Stratos Christianakis; Daniel G Arkfeld; Wendy J Mack; Martin Heur; William Stohl; Sarah F Hamm-Alvarez Journal: Sci Rep Date: 2018-07-23 Impact factor: 4.379