Subject(s)
Psoriasis/drug therapy , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Adult , Biopsy , Dose-Response Relationship, Drug , Double-Blind Method , Humans , Middle Aged , Piperidines , Psoriasis/immunology , Psoriasis/pathology , Pyrimidines/adverse effects , Pyrroles/adverse effectsABSTRACT
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.
Subject(s)
Quinoxalines/pharmacokinetics , Receptors, Chemokine/antagonists & inhibitors , Administration, Oral , Adolescent , Adult , Area Under Curve , Cross-Over Studies , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Cyclosporine/pharmacokinetics , Dizziness/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Drug Interactions , Fasting , Half-Life , Humans , Male , Metabolic Clearance Rate , Molecular Structure , Quinoxalines/administration & dosage , Quinoxalines/adverse effects , Receptors, CCR1ABSTRACT
Chemokines are 8- to 10-kDa proteins that regulate leukocyte infiltration into inflammatory sites. The therapeutic potential of inhibiting these proteins is supported by their increased expression in human diseases, numerous studies in animal models of disease and, in some cases, by human genetic association studies. These findings, combined with the ability of chemokines to interact with 7-transmembrane G protein-coupled receptors, render them attractive drug discovery targets. This article reviews the evidence that supports a role for the chemokine receptor CCR1 in the pathogenesis of autoimmune diseases, progress made in identifying low molecular-weight antagonists and the current status of agents undergoing clinical evaluation.
