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.
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.
Miyazawa
Keisuke
K
First Department of Internal Medicine (Hematology/Oncology), Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. miyazawa@tokyo-med.ac.jp.
Ohyashiki
Kazuma
K
First Department of Internal Medicine (Hematology/Oncology), Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
Urabe
Akio
A
NTT Kanto Medical Center, Tokyo, Japan.
Hata
Tomoko
T
Nagasaki University, Nagasaki, Japan.
Nakao
Shinji
S
Kanazawa University, Ishikawa, Japan.
Ozawa
Keiya
K
Jichi Medical University, Tochigi, Japan.
Ishikawa
Takayuki
T
Kyoto University, Kyoto, Japan.
Kato
Junji
J
Sapporo Medical University, Sapporo, Japan.
Tatsumi
Yoichi
Y
Kinki University, Osaka, Japan.
Mori
Hiraku
H
Showa University Fujigaoka Hospital, Yokohama, Japan.
Kondo
Midori
M
Novartis Pharma K.K., Tokyo, Japan.
Taniguchi
Junsuke
J
Novartis Pharma K.K., Tokyo, Japan.
Tanii
Hiromi
H
Novartis Pharma K.K., Tokyo, Japan.
Rojkjaer
Lisa
L
Novartis Pharma A.G., Basel, Switzerland.
Omine
Mitsuhiro
M
Showa University Fujigaoka Hospital, Yokohama, Japan.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic / Q000378:metabolism / Q000628:therapy*; D044466:Asian People; D001565:Benzoates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001803:Blood Transfusion; D000077588:Deferasirox; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019190:Iron Overload / Q000188:drug therapy* / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism / Q000628:therapy*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D000077588:Deferasirox