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

Abstract

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: Alan T Clucas, Ajit Shah, Yuanchao Derek Zhang, Vincent F Chow, Ronald P Gladue
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 46 Issue 9 Pg. 757-66 ( 2007) ISSN: 0312-5963 [Print] Switzerland
• PMID: 17713973 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• CCR1 protein, human
• Quinoxalines
• Receptors, CCR1
• Receptors, Chemokine
• quinoxaline-2-carboxylic acid (4-carbamoyl-1-(3-fluorobenzyl)-2,7-dihydroxy-7-methyloctyl)amide
• Cyclosporine

Topics

• Administration, Oral
• Adolescent
• Adult
• Area Under Curve
• Cross-Over Studies
• Cyclosporine (administration & dosage, adverse effects, 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, adverse effects, pharmacokinetics)
• Receptors, CCR1
• Receptors, Chemokine (antagonists & inhibitors)