Absence of an effect of a single-dose deferasirox on the steady-state pharmacokinetics of digoxin.

Author(s): Sechaud R, Robeva A, Belleli R, Balez S

Affiliation(s): Novartis Pharma AG, Basel, Switzerland. romain.sechaud@novartis.com

Publication date & source: 2008-10, Int J Clin Pharmacol Ther., 46(10):519-26.

Publication type: Randomized Controlled Trial; Research Support, Non-U.S. Gov't

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.