Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715

Background and objectives: The chemokine receptor CCR I 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 3000mg 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 300mg 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 300mg 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-1 alpha , 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 11 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.