title: Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies.
abstract: OBJECTIVE
  Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects.
  
  
  METHODS
  The OC study was a crossover study over two 28-day treatment periods (Microgynon(®) 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8-20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout.
  
  
  RESULTS
  Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration-time curve at steady state (AUCss) 28% [confidence interval (CI 90%) 21-36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34% (CI 26-43)], but not levonorgestrel (AUCss 5%; Cmax,ss -3%), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈ 20%). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18% (CI 13-23) and 13% (CI 7-19)]. Fostamatinib increased rosuvastatin AUC by 96% (CI 78-115) and Cmax by 88% (CI 69-110), and increased simvastatin acid AUC by 74% (CI 50-102) and Cmax by 83% (CI 57-113).
  
  
  CONCLUSIONS
  Fostamatinib exhibits drug-drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TF, Macclesfield, Cheshire, UK. paul.martin@astrazeneca.com.
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca, Wilmington, DE, USA. Michael.gillen@astrazeneca.com.
authors.forename: M
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Quintiles Drug Research Unit, Guy's Hospital, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Quintiles Phase I Unit, 6700 W 115th St, Overland Park, KS, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mathews
authors.affiliation: Former-AstraZeneca, Macclesfield, Cheshire, UK.
authors.forename: C
authors.initials: C
authors.lastname: Brealey
authors.affiliation: Former-AstraZeneca, Macclesfield, Cheshire, UK.
authors.forename: D
authors.initials: D
authors.lastname: Surry
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TF, Macclesfield, Cheshire, UK.
authors.forename: S
authors.initials: S
authors.lastname: Oliver
authors.affiliation: AstraZeneca, Cambridge, Cambridgeshire, UK.
authors.forename: V
authors.initials: V
authors.lastname: Holmes
authors.affiliation: Covance, Madison, WI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Severin
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, SK10 4TF, Macclesfield, Cheshire, UK.
authors.forename: R
authors.initials: R
authors.lastname: Elsby
mesh_terms: D000328:Adult; D000631:Aminopyridines; D019540:Area Under Curve; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium / Q000493:pharmacokinetics*; D019821:Simvastatin / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000631:Aminopyridines; D003277:Contraceptives, Oral, Combined; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D014859:Warfarin; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; C523665:fostamatinib