BACKGROUND AND OBJECTIVES: The chemokine receptor CCR1 is believed to play a role in several inflammatory diseases, primarily by promoting the migration of leukocytes through the endothelial barrier. Thus, a possible strategy for treating inflammatory diseases is inhibition of leukocyte infiltration by antagonising CCR1. Recently, CP-481,715 has been described as a potent and specific antagonist of CCR1. The aims of this study were to assess the safety, pharmacokinetics and pharmacodynamics of CP-481,715 along with drug interactions with ciclosporin. SUBJECTS AND METHODS: This was a phase I randomised, double-blind, placebo-controlled study with CP-481,715 in 78 healthy male volunteers. Subjects were administered escalating CP-481,715 doses of up to 3000 mg with food and after fasting in the single-dose study. In the drug interaction study, which was a single-dose, two-way crossover study, 12 subjects received a 300 mg dose of CP-481,715 as a suspension of polymorph A under fasted conditions, both with and without prior administration of ciclosporin. RESULTS AND CONCLUSIONS: All doses of CP-481,715 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of CP-481,715 was detected ex vivo by demonstrating a dose-related and linear increase in the amount of macrophage inflammatory protein-1alpha, CCL3, required to induce CD11b upregulation. Analysis of vital signs indicated no consistent clinical effects, and statistical analysis of ECG characteristics demonstrated no significant prolongation of the corrected QT interval. A drug-drug interaction study with ciclosporin demonstrated that CP-481,715 clearance was decreased by ciclosporin, consistent with its ability to compete with P-glycoprotein. Phase II studies may be warranted to see if CP-481,715 exhibits efficacy in treating inflammatory diseases such as rheumatoid arthritis, multiple sclerosis or transplant rejection.
RCT Entities:
BACKGROUND AND OBJECTIVES: The chemokine receptor CCR1 is believed to play a role in several inflammatory diseases, primarily by promoting the migration of leukocytes through the endothelial barrier. Thus, a possible strategy for treating inflammatory diseases is inhibition of leukocyte infiltration by antagonising CCR1. Recently, CP-481,715 has been described as a potent and specific antagonist of CCR1. The aims of this study were to assess the safety, pharmacokinetics and pharmacodynamics of CP-481,715 along with drug interactions with ciclosporin. SUBJECTS AND METHODS: This was a phase I randomised, double-blind, placebo-controlled study with CP-481,715 in 78 healthy male volunteers. Subjects were administered escalating CP-481,715 doses of up to 3000 mg with food and after fasting in the single-dose study. In the drug interaction study, which was a single-dose, two-way crossover study, 12 subjects received a 300 mg dose of CP-481,715 as a suspension of polymorph A under fasted conditions, both with and without prior administration of ciclosporin. RESULTS AND CONCLUSIONS: All doses of CP-481,715 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of CP-481,715 was detected ex vivo by demonstrating a dose-related and linear increase in the amount of macrophage inflammatory protein-1alpha, CCL3, required to induce CD11b upregulation. Analysis of vital signs indicated no consistent clinical effects, and statistical analysis of ECG characteristics demonstrated no significant prolongation of the corrected QT interval. A drug-drug interaction study with ciclosporin demonstrated that CP-481,715 clearance was decreased by ciclosporin, consistent with its ability to compete with P-glycoprotein. Phase II studies may be warranted to see if CP-481,715 exhibits efficacy in treating inflammatory diseases such as rheumatoid arthritis, multiple sclerosis or transplant rejection.
Authors: S C Lee; M E Brummet; S Shahabuddin; T G Woodworth; S N Georas; K M Leiferman; S C Gilman; C Stellato; R P Gladue; R P Schleimer; L A Beck Journal: J Immunol Date: 2000-03-15 Impact factor: 5.422
Authors: Ronald P Gladue; Laurie A Tylaska; William H Brissette; Paul D Lira; John C Kath; Christopher S Poss; Matthew F Brown; Timothy J Paradis; Maryrose J Conklyn; Kevin T Ogborne; Molly A McGlynn; Brett M Lillie; Amy P DiRico; Erin N Mairs; Eric B McElroy; William H Martin; Ingrid A Stock; Richard M Shepard; Henry J Showell; Kuldeep Neote Journal: J Biol Chem Date: 2003-08-07 Impact factor: 5.157
Authors: Ryan A Wilcox; David A Wada; Steven C Ziesmer; Sherine F Elsawa; Nneka I Comfere; Allan B Dietz; Anne J Novak; Thomas E Witzig; Andrew L Feldman; Mark R Pittelkow; Stephen M Ansell Journal: Blood Date: 2009-08-11 Impact factor: 22.113