Document Detail


Pharmacokinetics of Fostamatinib, a SYK Inhibitor, in Healthy Human Subjects Following Single and Multiple Oral Dosing In Three Phase I Studies.
MedLine Citation:
PMID:  23190017     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: Fostamatinib (R788) is an orally-dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406. METHODS: Three clinical studies were conducted in healthy subjects: (A) A single ascending-dose study for R406 with doses ranging from 80-600 mg, (B) A single and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400 mg and multiple doses at 160 mg bid, and (C) A study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states. RESULTS: These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12-21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension, and steady-state was achieved after 3-4 days following twice-daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon coadministration with food, a delay in peak time and lower peak concentrations of R406 were observed, at the same time the overall exposure did not change. CONCLUSIONS: Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once-daily or twice-daily oral administration of fostamatinib.
Authors:
Muhammad Baluom; Elliott B Grossbard; Tim Mant; David T W Lau
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-29
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  -     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd, South San Francisco, CA, USA.
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