Garcia-Manero G, Stoltz M L, Ward M R, Kantarjian H, Sharma S
Department of Leukemia, University of Texas M D Anderson Cancer, Houston, TX 77030, USA.
Leukemia. 2008 Sep;22(9):1680-4. doi: 10.1038/leu.2008.145. Epub 2008 Jun 12.
Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m(2) for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.
阿扎胞苷是胞苷的嘧啶核苷类似物，具有去甲基化和抗白血病活性。已证明阿扎胞苷对高危骨髓增生异常综合征（MDS）患者有生存益处，并对急性髓性白血病（AML）有治疗活性。它通过皮下（s.c.）或静脉内（i.v.）注射给药，剂量为75mg/m²，每天一次，共7天，每4周重复一次。口服制剂将便于给药，减少给药副作用，并可能使阿扎胞苷的药理作用最大化。此前，这类药物的口服制剂因胞苷脱氨酶快速分解代谢以及在水性环境中水解而失败。薄膜包衣制剂的开发克服了这一困难。在一项制剂可行性初步研究中，4名患有实体恶性肿瘤、AML或MDS的受试者接受了60或80mg阿扎胞苷的单次口服剂量。受试者的血浆阿扎胞苷浓度可测，从而能够与皮下注射阿扎胞苷的历史药代动力学数据进行生物利用度比较。受试者安全耐受80mg剂量，该剂量的平均生物利用度为皮下注射阿扎胞苷历史暴露量的17.4%。未观察到严重的药物相关毒性。这些数据表明口服阿扎胞苷在人体中具有生物利用度，应在正式的1期试验中进行研究。
