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Pharmacokinetic and Pharmacodynamic Evaluation of the Novel CCR1 Antagonist CCX354 in Healthy Human Subjects: Implications for Selection of Clinical Dose
- Source :
- Clinical Pharmacology & Therapeutics. 89:726-734
- Publication Year :
- 2011
- Publisher :
- Springer Science and Business Media LLC, 2011.
-
Abstract
- 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
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15326535 and 00099236
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Clinical Pharmacology & Therapeutics
- Accession number :
- edsair.doi.dedup.....3b23d5e449093c08b90fee2b6b277264