title: Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin.
abstract: BACKGROUND
  Coronary heart disease, stroke, and peripheral vascular disease are the most common causes of mortality in patients with type 2 diabetes mellitus (T2DM). The aim of these studies was to assess the potential for pharmacokinetic interaction between dapagliflozin, a sodium glucose co-transporter-2 inhibitor being developed for the treatment of T2DM, and four medications commonly prescribed in patients with T2DM and cardiovascular disease: simvastatin, valsartan, warfarin, and digoxin.
  
  
  METHODS
  Potential pharmacokinetic interactions between 20 mg dapagliflozin, 40 mg simvastatin, or 320 mg valsartan were assessed in an open-label, randomized, five-period, five-treatment, unbalanced crossover study in 24 healthy subjects. In a second study, the effects of steady-state dapagliflozin on the pharmacokinetics of 25 mg warfarin or 0.25 mg digoxin were assessed in an open-label, randomized, two-period, two-treatment crossover study in 30 healthy subjects divided into two cohorts. The potential pharmacodynamic interaction between dapagliflozin and warfarin was also evaluated.
  
  
  RESULTS
  All treatments were well tolerated. Neither simvastatin nor valsartan had any clinically meaningful effect on the pharmacokinetics of dapagliflozin. Dapagliflozin increased the area under the curve for simvastatin, simvastatin acid, and valsartan by approximately 19%, 30%, and 6%, respectively, and decreased the maximum observed plasma concentration of valsartan by approximately 6%. These effects were not considered clinically meaningful. In addition, dapagliflozin had no effect on the pharmacokinetics of either digoxin or warfarin. The pharmacodynamics of warfarin were also unaffected by dapagliflozin.
  
  
  CONCLUSIONS
  In these studies the co-administration of dapagliflozin and simvastatin, valsartan, warfarin, or digoxin was well tolerated without clinically meaningful drug-drug interaction.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. sreeneeranj.kasichayanula@bms.com
authors.forename: Sreeneeranj
authors.initials: S
authors.lastname: Kasichayanula
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Liu
authors.forename: Wen-Chyi
authors.initials: WC
authors.lastname: Shyu
authors.forename: Steven C
authors.initials: SC
authors.lastname: Griffen
authors.forename: Frank P
authors.initials: FP
authors.lastname: LaCreta
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
mesh_terms: D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics; D000925:Anticoagulants / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000493:pharmacokinetics; D001559:Benzhydryl Compounds; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004077:Digoxin / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005960:Glucosides / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000493:pharmacokinetics; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013777:Tetrazoles / Q000493:pharmacokinetics; D014633:Valine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000068756:Valsartan; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D000889:Anti-Arrhythmia Agents; D000924:Anticholesteremic Agents; D000925:Anticoagulants; D000959:Antihypertensive Agents; D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013777:Tetrazoles; C529054:dapagliflozin; D014859:Warfarin; D004077:Digoxin; D000068756:Valsartan; D019821:Simvastatin; D014633:Valine