title: Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor.
abstract: BACKGROUND
  Apixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects.
  
  
  METHODS
  This two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated.
  
  
  RESULTS
  Famotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUC∞). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUC∞ (1.007), and 90% confidence intervals were entirely contained within the 80%-125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated.
  
  
  CONCLUSIONS
  Famotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due to underlying conditions (eg, achlorhydria), or by gastrointestinal pH-mediated effects of other histamine H2-receptor antagonists, antacids, or proton pump inhibitors. Given that famotidine is also an inhibitor of the human organic cation transporter (hOCT), these results indicate that apixaban pharmacokinetics are not influenced by hOCT uptake transporter inhibitors. Overall, these results support that apixaban can be administered without regard to coadministration of gastric acid modifiers.
authors: Clinical Pharmacology and Pharmacometrics, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Princeton, NJ, USA.
authors: Vijay V
authors: VV
authors: Upreti
authors: Yan
authors: Y
authors: Song
authors: Jessie
authors: J
authors: Wang
authors: Wonkyung
authors: W
authors: Byon
authors: Rebecca A
authors: RA
authors: Boyd
authors: Janice M
authors: JM
authors: Pursley
authors: Frank
authors: F
authors: Lacreta
authors: Charles E
authors: CE
authors: Frost
keywords: H2-receptor antagonists; apixaban; drug–drug interaction; factor Xa inhibitor; famotidine; hOCT inhibitor
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