title: Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies.
abstract: OBJECTIVE
  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 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.
  
  
  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.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080, USA. mbaluom@rigel.com
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baluom
authors.forename: Elliott B
authors.initials: EB
authors.lastname: Grossbard
authors.forename: Tim
authors.initials: T
authors.lastname: Mant
authors.forename: David T W
authors.initials: DT
authors.lastname: Lau
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000631:Aminopyridines; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019999:Pharmaceutical Solutions; D011355:Prodrugs; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines; D013535:Suspensions; D000072377:Syk Kinase; D013607:Tablets; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D019999:Pharmaceutical Solutions; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013535:Suspensions; D013607:Tablets; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib