title: Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a P-Glycoprotein Substrate): Results From in Vitro and Phase I Clinical Studies.
abstract: OBJECTIVE
  Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of fostamatinib on the pharmacokinetic parameters of digoxin to understand drug-drug interaction (DDI) potential in the clinic.
  
  
  METHODS
  Inhibition of P-gp-mediated digoxin transport by fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC50) and theoretical gastrointestinal concentration [I2] (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration-time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral fostamatinib 100 mg BID on days 9 to 15.
  
  
  RESULTS
  Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC50 = 3.2 μM). On the basis of a theoretical gastrointestinal concentration (I2)/IC50 ratio of 216 ([I2] = 691 μM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70-fold increase in digoxin maximum plasma concentration at steady state (Cmax,ss) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of Cmax was earlier when digoxin was co-administered with fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported.
  
  
  CONCLUSIONS
  Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354.
authors.affiliation: AstraZeneca, London, United Kingdom. Electronic address: paul.martin@astrazeneca.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca, Wilmington, Delaware.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: AstraZeneca, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Millson
authors.affiliation: AstraZeneca, London, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.affiliation: AstraZeneca, London, United Kingdom.
authors.forename: Clive
authors.initials: C
authors.lastname: Brealey
authors.affiliation: AstraZeneca, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Elsby
authors.affiliation: Rigel Pharmaceuticals Inc, South San Francisco, California.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baluom
authors.affiliation: Rigel Pharmaceuticals Inc, South San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Lau
authors.affiliation: Quintiles Drug Research Unit, Guy's Hospital, London, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Mant
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000631:Aminopyridines; D018938:Caco-2 Cells; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011743:Pyrimidines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000631:Aminopyridines; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D004077:Digoxin; C523665:fostamatinib
keywords: digoxin; drug interaction; fostamatinib; pharmacokinetic parameters; rheumatoid arthritis