Document Detail


Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies.
MedLine Citation:
PMID:  23190017     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIM: 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.
METHOD: 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 twice daily 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 co-administration with food, a delay in peak time and lower peak concentrations of R406 were observed but at the same time the overall exposure did not change.
CONCLUSION: 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:  Clinical Trial, Phase I; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  76     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-20     Completed Date:  2014-02-03     Revised Date:  2014-07-01    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  78-88     Citation Subset:  IM    
Copyright Information:
© 2012 Rigel Pharmaceuticals, Inc.. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Adolescent
Adult
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Female
Food-Drug Interactions
Half-Life
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Male
Middle Aged
Oxazines / administration & dosage,  pharmacokinetics*
Pharmaceutical Solutions
Prodrugs
Protein Kinase Inhibitors / administration & dosage,  pharmacokinetics*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Pyridines / administration & dosage,  pharmacokinetics*
Suspensions
Tablets
Young Adult
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; 0/Oxazines; 0/Pharmaceutical Solutions; 0/Prodrugs; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/Suspensions; 0/Tablets; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Syk kinase; SQ8A3S5101/fostamatinib
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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