title: Pharmacokinetic Properties of Fostamatinib in Patients With Renal or Hepatic Impairment: Results From 2 Phase I Clinical Studies.
abstract: OBJECTIVE
  Phase III trials of fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide.
  
  
  METHODS
  Two Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of fostamatinib in subjects with normal or impaired renal or hepatic function. Twenty-four subjects in the study in renal impairment (8 per group: normal renal function, moderate renal dysfunction, or end-stage renal disease [ESRD]), and 32 subjects in the study in hepatic impairment (8 per group: normal hepatic function or mild, moderate, or severe hepatic impairment) received a single 150-mg dose of fostamatinib. Patients with ESRD in the study in renal impairment participated in 2 treatment periods separated by a ≥1-week washout. In these patients, fostamatinib was administered after dialysis or 2 hours before dialysis.
  
  
  RESULTS
  Geometric mean R406 Cmax and AUC values were less in the combined renally impaired group than in the group with normal renal function; Tmax was similar across groups. However, renal impairment had no apparent effect considered clinically relevant on unbound R406. In patients with ESRD, R406 exposure was less when fostamatinib was administered after compared with before dialysis. Urinary excretion of R406 N-glucuronide was decreased with increasing severity of renal impairment. Renal elimination of R406 was negligible in all groups. Varying degrees of hepatic impairment had no consistent effects on the PK properties of R406. R406 Cmax values were 10% to 15% less in all hepatically impaired groups than in the group with normal hepatic function. AUC and Tmax values were similar between the groups with normal and severely impaired hepatic function; in the groups with mild or moderate hepatic impairment, AUC was less and Tmax was greater. The geometric mean percentage of unbound R406 ranged from 0.64% to 1.95% and was greatest in the group with severe hepatic impairment. The urinary excretion of R406 was minimal. The amount of R406 N-glucuronide excreted in urine was greater in severely hepatically impaired patients. Fostamatinib 150 mg was generally well tolerated.
  
  
  CONCLUSIONS
  In these patients, renal or hepatic impairment did not affect exposure to the active metabolite of fostamatinib, R406, to a clinically relevant extent. ClinicalTrials.gov identifiers: NCT01245790 (renal) and NCT01222455 (hepatic).
authors.affiliation: AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom. Electronic address: paul.martin@astrazeneca.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, Delaware.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Orlando Clinical Research Center, Orlando, Florida.
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.affiliation: AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Millson
mesh_terms: D000631:Aminopyridines; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines
chemical_list: D000631:Aminopyridines; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C523665:fostamatinib
keywords: fostamatinib; hepatic impairment; pharmacokinetics; renal impairment; rheumatoid arthritis