Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes
Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes
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DOI：
10.1111/j.1349-7006.2011.01993.x
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发表时间：
2011-09-01
期刊：
影响因子：
5.7
通讯作者：
Hotta, Tomomitsu
中科院分区：
文献类型：
--
作者：
Uchida, Toshiki;Ogawa, Yoshiaki;Hotta, Tomomitsu
阿扎胞苷是一种DNA甲基转移酶抑制剂，据报道具有抗白血病疗效，并在西方国家被批准用于治疗骨髓增生异常综合征。我们在日本骨髓增生异常综合征患者中进行了阿扎胞苷的I/II期研究，以评价其药代动力学、疗效和安全性。共有53例患者接受阿扎胞苷75 mg/m2皮下注射或静脉注射，每日1次，连续7天，28天为1周期。静脉给药后的C（max）约为皮下给药后的3.7倍，而皮下和静脉给药从时间0至无穷大的血药浓度-时间曲线下面积相当。皮下给药后阿扎胞苷的生物利用度为91.1%，表明皮下给药后阿扎胞苷几乎完全吸收。血液学改善率和血液学缓解率分别为54.9%（28/51）和28.3%（15/53），两种给药途径之间无差异。阿扎胞苷在日本骨髓增生异常综合征患者中耐受性良好，临床可管理。20%的患者发生的不良事件包括血液学毒性、胃肠道事件和全身性疾病，如不适。50%患者发生的3/4级不良事件均由血液学毒性引起。除皮下给药后观察到的注射部位反应外，阿扎胞苷两种给药途径的安全性特征基本相似。这些结果表明，阿扎胞苷可以预期是一个有用的治疗药物在日本骨髓增生异常综合征患者。（《癌症科学》2011; 102：1680-1686）
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. (Cancer Sci 2011; 102: 1680-1686)