title: Absence of an effect of a single-dose deferasirox on the steady-state pharmacokinetics of digoxin.
abstract: Deferasirox (Exjade, ICL670) is a potent iron chelator, recently approved as first-line therapy for the treatment of blood-transfusion-related iron overload. Iron deposition in the heart may lead to cardiac dysfunction in patients with iron overload. Thus, the combination of cardiac glycosides and deferasirox is likely to be used in clinical practice.
  
  
  OBJECTIVE
  This study was designed to investigate the effect of deferasirox on steady-state pharmacokinetics of digoxin. As digoxin is a P-glycoprotein substrate, the trial also explored the potential of deferasirox to alter the pharmacokinetics of compounds transported by P-glycoprotein in general.
  
  
  METHODS
  An open-label, randomized, 2-period, crossover study was carried out with 16 healthy volunteers. During both treatment periods, each subject received daily oral doses of digoxin for 8 days (0.5 mg on Day 1 and 0.25 mg/day on Days 2 - 8). In one of these treatment periods, single oral deferasirox 20 mg/kg was coadministered with digoxin on Day 8. Pharmacokinetic parameters assessed at the end of each treatment period were compared using the standard statistical analysis for bioequivalence assessment.
  
  
  RESULTS
  Deferasirox did not alter the steady-state pharmacokinetics of digoxin. The geometric mean ratios and 90% confidence intervals for Cmax and AUCtau of digoxin (with/without deferasirox) were 0.93 (0.82 - 1.06) and 0.91 (0.83 - 1.00), respectively, and thus within the equivalence limits of 0.8 - 1.25. The amount of digoxin excreted intact in urine was similarly unaltered by coadministration of deferasirox.
  
  
  CONCLUSIONS
  This study shows that single-dose deferasirox has no effect on steady-state pharmacokinetics of digoxin. Therefore, no dose adjustment of digoxin is necessary when deferasirox and digoxin are coadministered. The lack of interaction suggests that deferasirox is unlikely to interact with P-glycoprotein substrates.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. romain.sechaud@novartis.com
authors.forename: R
authors.initials: R
authors.lastname: Sechaud
authors.forename: A
authors.initials: A
authors.lastname: Robeva
authors.forename: R
authors.initials: R
authors.lastname: Belleli
authors.forename: S
authors.initials: S
authors.lastname: Balez
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D018592:Cross-Over Studies; D000077588:Deferasirox; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D001565:Benzoates; D002316:Cardiotonic Agents; D007502:Iron Chelating Agents; D014230:Triazoles; D004077:Digoxin; D000077588:Deferasirox