title: Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes.
abstract: Azacitidine, an inhibitor of DNA methyltransferase, is reported to have antileukemic efficacy and is approved for the treatment of myelodysplastic syndromes in Western countries. We have conducted a Phase I/II study of azacitidine in Japanese patients with myelodysplastic syndromes to evaluate its pharmacokinetics, efficacy, and safety. In all, 53 patients received 75 mg/m(2) azacitidine subcutaneously or intravenously once daily for seven consecutive days on a 28-day cycle. The C(max) following intravenous administration was approximately 3.7-fold higher than that following subcutaneous administration, whereas the area under the plasma concentration-time curve from time zero to infinity was comparable for subcutaneous and intravenous administration. The bioavailability of azacitidine following subcutaneous administration was 91.1%, indicating that azacitidine is nearly completely absorbed after subcutaneous administration. The hematologic improvement and hematologic response rates were 54.9% (28/51) and 28.3% (15/53), respectively, and there were no differences between the two routes of administration. Azacitidine was generally well tolerated and clinically manageable in Japanese patients with myelodysplastic syndromes. Adverse events occurred in ≥ 20% of patients included hematologic toxicity, gastrointestinal events, and general disorders, such as malaise. Grade 3/4 adverse events that occurred in ≥ 50% of patients were all due to hematologic toxicity. The safety profile of azacitidine was generally similar for both routes of administration, with the exception of injection site reactions observed following subcutaneous administration. These results indicate that azacitidine can be expected to be a useful therapeutic agent in Japanese patients with myelodysplastic syndromes.
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan. tuchida@nagoya2.jrc.or.jp
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchida
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Ohashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hata
authors.forename: Noriko
authors.initials: N
authors.lastname: Usui
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Hideki
authors.initials: H
authors.lastname: Akiyama
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomita
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hotta
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D001374:Azacitidine