title: Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of fostamatinib: results from five phase I clinical studies.
abstract: OBJECTIVE
  Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability.
  
  
  METHODS
  A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability.
  
  
  RESULTS
  The in vivo performance of fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of fostamatinib was 54.6 %.
  
  
  CONCLUSIONS
  The absolute oral bioavailability of fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Talia
authors.initials: T
authors.lastname: Flanagan
authors.affiliation: Sandoz, Industriestrasse 25, Holzkirchen, Germany. paul-1.martin@sandoz.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca, One MedImmune Way, Gaithersburg, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Quintiles Inc., 6700 W. 115th St, Overland Park, KS, 66211, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mathews
authors.affiliation: Quintiles Inc., 6700 W. 115th St, Overland Park, KS, 66211, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Lisbon
authors.affiliation: LEO Pharma, Industriparken 55, 2750, Ballerup, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Kruusmägi
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000631:Aminopyridines; D000863:Antacids / Q000737:chemistry / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002482:Cellulose / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D005502:Food; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines; D011899:Ranitidine / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D000072377:Syk Kinase / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D000863:Antacids; D000897:Anti-Ulcer Agents; D009025:Morpholines; D010078:Oxazines; D011355:Prodrugs; D011725:Pyridines; D011743:Pyrimidines; D011899:Ranitidine; D002482:Cellulose; D000072377:Syk Kinase; C109691:microcrystalline cellulose; C523665:fostamatinib
keywords: Absolute bioavailability; Food effect; Fostamatinib; Pharmacokinetics; Ranitidine DDI; SYK inhibitor