A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade®, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan

Abstract

The pharmacokinetics (PK) and pharmacodynamics (PD) of the once-daily, oral ironchelating agent, deferasirox (Exjade, ICL670), have been evaluated further in a Phase I, openlabel, multicenter, dose-escalation study in Japanese patients with myelodysplastic syndromes, aplastic anemia, and other anemias. Deferasirox was initially administered as a single dose of 5 (n = 6), 10 (n = 7), 20 (n = 6) or 30 (n = 7) mg/(kg day) and then after 7 days seven daily doses were administered. Linear PK (C (max) and AUC) were observed at all doses after a single dose and at steady state, and dose-dependent iron excretion was observed. Pharmacokinetic/pharmacodynamic parameters were similar to those reported in a Caucasian beta-thalassemia cohort. Following the single- and multiple-dose phases, 21 of 26 patients progressed to a 3-year extension phase of the study, where dose reductions and increases [5-30 mg/(kg day)] were allowed following safety and efficacy assessments. In the interim, 1-year data show that deferasirox was well tolerated, with generally infrequent and mild adverse events. Reductions in serum ferritin levels were observed and a negative iron balance achieved at doses of 20-30 mg/(kg day). These data suggest that deferasirox has a stable and predictable PK/PD profile, irrespective of underlying disease or race, and a predictable and manageable safety profile suitable for chronic administration.

Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox

“…Thus far, there are limited data on largescale evaluation of iron chelation practice especially in terms of its clinical efficacy and safety profile in the Asian population [12]. To date, most studies were hampered by small sample sizes and the limited numbers of patients representative of the different ethnic origins found in this region [13][14][15][16] Deferasirox, a novel once-daily oral iron chelator, has been available for use in clinical practice since 2005 for the treatment of transfusional iron overload in adult and paediatric patients at least 2 years of age. The efficacy and safety of deferasirox in thalassaemia patients has been well-documented [17][18][19][20].…”

“…The efficacy and safety of deferasirox in thalassaemia patients has been well-documented [17][18][19][20]. However, most of the previous trials were conducted in thalassaemia patients outside the AP region and data on its use in the region is rather limited [16]. In addition, recent data from Thailand showed that local thalassaemia patients appeared to develop a significantly higher rate of mild cutaneous rashes with deferasirox exposure than what has been reported in the literature (18% Thai vs. 10-11% Caucasian patients) [17,19,21].…”

Effect of iron chelator deferasirox on chronic anemia and thrombocytopenia in a transfusion-dependent patient with myelodysplastic syndrome

“…However, Takatoku et al [1] reported that only 8.6% of Japanese patients with transfusion iron overload were treated with effective daily or continuous administration of deferoxamin, which must be applied as a continuous subcutaneous infusion and often results in poor compliance. Recently, the use of a novel once-daily oral chelator, deferasirox, was approved in Japan, and it is providing effective convenient therapy with safety and tolerability [2]. Herein, we report a case of a transfusiondependent MDS patient with iron overload, who was successfully treated with deferasirox, resulting in not only reduced iron level of serum ferritin, but also decrease in red blood cell (RBC) transfusion requirement and suspension of platelet (PC) transfusion.…”

Restoration of cardiac function by an iron chelator, deferasirox, in a patient with aplastic anemia and cardiac iron overload

“…She had received intermittent intravenous deferoxamine (500 mg per week) from July 1996, but her serum ferritin level gradually increased. The patient was enrolled in a Phase I study of deferasirox in July 2005 [4]. At the time, serum ferritin was elevated to 17,000 ng/mL.…”