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.

The laser Raman spectra of lyophilized spores of 5 species (6 strains) of Bacillus were examined. Under the experimental conditions employed, only Bacillus megaterium species showed 3 intense Raman bands at 1515, 1157 and 1007 cm−1. Spores of other species, despite their high content of dipicolinic acid, did not show distinct Raman signals. The strong, scattering bands at 1515 and 1157 cm−1 in the spectra of spores of B. megaterium may be attributable to conjugated double‐bond systems, probably of membrane‐associated carotenoids. Their high intensities are due to resonance enhancement.

Introduction: In Japan, myelodysplastic syndromes (MDS) and aplastic anemia (AA) are the most common transfusion-dependent anemias. Deferasirox (Exjade®, ICL670) is a once-daily, oral iron chelator for the treatment of transfusional iron overload; its efficacy and tolerability have been established in adults and children with a range of transfusion-dependent anemias, including MDS. Here, deferasirox has been evaluated in Japanese patients and the pharmacokinetics (PK) and pharmacodynamics (PD) compared with those seen in a US study. Methods: The tolerability, PK and PD of deferasirox have been assessed in a Phase I, open-label, unblinded, dose-escalation trial (1101) in Japanese patients with MDS and AA in 9 centers. Deferasirox was administered as a single dose of 5 (n=6), 10 (n=7), 20 (n=6) or 30 mg/kg (n=7). After a 7-day break, daily doses were administered (same doses/same patients) for 7 consecutive days. Data were compared with a study (0104) in 24 Caucasian β-thalassemia patients (age range 18–39 years) who were administered doses of deferasirox of 10, 20 or 40 mg/kg/day for 12 days. Throughout the study, iron intake and excretion were rigorously measured. Results: A total of 26 Japanese patients (8 male, 18 female; mean age 65.6 years; 8 aged <65 years) completed single- and multiple-dosing periods (16 MDS; 6 AA; 4 other anemias). After a single dose and also at steady state, linear PK (Cmax and AUC) were observed at all doses. The figures show Cmax and AUC at steady state for both the Japanese patients (closed circles, solid lines) and the Caucasian patients (open squares, dotted lines), and demonstrate that PK were similar. Figure Figure Dose-dependent iron excretion (range 0.07–0.61 mg iron/kg/day) was observed, similar to that in the Caucasian patients (range 0.12–0.45 mg iron/kg/day). A linear relationship (PK/PD) was noted between AUC and iron excretion. Deferasirox was well tolerated, with generally infrequent and mild adverse events (AEs). The most common AEs related to deferasirox were diarrhea (n=2 each after single and multiple doses of 30 mg/kg/day) and nausea (n=1 each after multiple doses at 10 and 30 mg/kg/day). One patient had two serious AEs, pyrexia and duodenal ulcer, both suspected to be related to study drug, after multiple doses of 30 mg/kg/day. Conclusions: Deferasirox is well tolerated both after single and multiple doses in Japanese MDS/AA patients, with similar PK/PD parameters to those in the Caucasian β-thalassemia cohort. Exposure to deferasirox in the Japanese patient cohort was dose dependent with a linear PK/PD relationship resulting in dose-dependent iron excretion. These data suggest that deferasirox is effective and well tolerated regardless of underlying disease, race or age.