title: 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.
authors.affiliation: 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.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyazawa
authors.affiliation: First Department of Internal Medicine (Hematology/Oncology), Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
authors.affiliation: NTT Kanto Medical Center, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Urabe
authors.affiliation: Nagasaki University, Nagasaki, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hata
authors.affiliation: Kanazawa University, Ishikawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Jichi Medical University, Tochigi, Japan.
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.affiliation: Kyoto University, Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Sapporo Medical University, Sapporo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
authors.affiliation: Kinki University, Osaka, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Tatsumi
authors.affiliation: Showa University Fujigaoka Hospital, Yokohama, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Mori
authors.affiliation: Novartis Pharma K.K., Tokyo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Novartis Pharma K.K., Tokyo, Japan.
authors.forename: Junsuke
authors.initials: J
authors.lastname: Taniguchi
authors.affiliation: Novartis Pharma K.K., Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanii
authors.affiliation: Novartis Pharma A.G., Basel, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rojkjaer
authors.affiliation: Showa University Fujigaoka Hospital, Yokohama, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Omine
mesh_terms: 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*
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D000077588:Deferasirox