Pharmacokinetic and Pharmacodynamic Evaluation of the Novel CCR1 Antagonist CCX354 in Healthy Human Subjects: Implications for Selection of Clinical Dose
| Autor: | J. C. Jaen, AM Pennell, P Bekker, P. Zhang, Y. Wang, Y Zeng, Lisa Seitz, DJ Dairaghi, D.A. Johnson, S Miao, LS Ertl, T. J. Schall, J. P. Powers |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male medicine.medical_specialty Receptors CCR1 Pharmacology Monocytes law.invention Young Adult Double-Blind Method Pharmacokinetics law Quinoxalines Internal medicine Animals Humans Medicine Pharmacology (medical) Rats Wistar Receptor Whole blood Clinical pharmacology Dose-Response Relationship Drug business.industry Antagonist Middle Aged medicine.disease Rats Blockade Endocrinology Rheumatoid arthritis Pharmacodynamics Female Rabbits Inflammation Mediators business Protein Binding |
| Zdroj: | Clinical Pharmacology & Therapeutics. 89:726-734 |
| ISSN: | 1532-6535 0009-9236 |
| Popis: | The safety and pharmacokinetic (PK)/pharmacodynamic (PD) profile of the novel CCR1 antagonist CCX354 was evaluated in double-blind, placebo-controlled, single- and multiple-dose phase I studies (1–300 mg/day oral doses). CCX354 was well tolerated and displayed a linear dose–exposure profile, with half-life approaching 7 h at the 300-mg dose. The extent of CCR1 receptor blockade on blood monocytes, which correlated well with plasma concentrations of the drug, was assessed using fluorescently labeled CCL3 binding in whole blood from phase I subjects. High levels of receptor coverage at the 12-h time point were achieved after a single dose of 100 mg CCX354. Preclinical studies indicate that effective blockade of inflammatory cell infiltration into tissues requires ≥90% CCR1 inhibition on blood leukocytes at all times. The comparison of the properties of CCX354 with those published for other CCR1 antagonists has informed the dose selection for ongoing clinical development of CCX354 in rheumatoid arthritis (RA). Clinical Pharmacology & Therapeutics (2011) 89 5, 726–734. doi:10.1038/clpt.2011.33 |
| Databáze: | OpenAIRE |
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