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Phase I Evaluation of the Safety, Pharmacokinetics and Pharmacodynamics of CP-481,715

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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, placebocontrolled 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-1α, 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.

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Acknowledgements

Ajit Shah now works at MGI Pharma, Inc., Bloomington, MN, USA. Yuanchao (Derek) Zhang now works at the Center for Drug Evaluation and Research, US FDA, Rockville, MD, USA. The authors thank Dr Michael Seiberling of Swiss Pharma Contract for his contribution as principal investigator for the study, Ms Amy DiRico of Pfizer, Inc. for assistance in data collection, and Drs Albert Seymour and Stephanie Hall of Pfizer, Inc. for pharmacogenomic analyses.

Alan T. Clucas, Vincent F. Chow and Ronald P. Gladue are employees of Pfizer, Inc. and hold stock options in Pfizer, Inc. Ronald Gladue has received patents for CP-481,715 on behalf of Pfizer. Ajit Shah and Yuanchao Zhang were employees of Pfizer, Inc. at the time of the study, and Ajit Shah holds stock options in Pfizer, Inc. This work was entirely funded by Pfizer, Inc.

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Authors and Affiliations

  1. Pfizer Global Research and Development, 50 Pequot Avenue, New London, Connecticut, 06320, USA

    Alan T. Clucas, Ajit Shah, Yuanchao (Derek) Zhang, Vincent F. Chow & Ronald P. Gladue

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  1. Alan T. Clucas
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  2. Ajit Shah
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  5. Ronald P. Gladue
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Clucas, A.T., Shah, A., Zhang, Y.(. et al. Phase I Evaluation of the Safety, Pharmacokinetics and Pharmacodynamics of CP-481,715. Clin Pharmacokinet 46, 757–766 (2007). https://doi.org/10.2165/00003088-200746090-00003

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