口服的固定剂量组合decitabine和cedazuridine骨髓增生异常综合症:一项多中心、非盲、剂量递增,第一阶段学习。

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萨沃纳先生,Odenike O, Amrein PC,斯丁斯默DP, DeZern AE, Michaelis LC Faderl年代,Harb W, Kantarjian H, Lowder J, Oganesian, Azab M, Garcia-Manero G

口服的固定剂量组合decitabine和cedazuridine骨髓增生异常综合症:一项多中心、非盲、剂量递增,第一阶段学习。

柳叶刀Haematol。2019年4月,6 (4):e194-e203。doi: 10.1016 / s2352 - 3026 (19) 30030 - 4。

PubMed ID
30926081 (在PubMed
]
文摘

背景:Decitabine, DNA甲基转移酶1抑制剂或DNA hypomethylating化合物,不易口服生物利用率,因为快速清除胞嘧啶核苷脱氨酶(CDA)在肠道和肝脏。这剂量研究,指导下的药代动力学和药效学观察,评估是否同时口服与小说CDA抑制剂cedazuridine decitabine增加生物利用度治疗骨髓增生异常综合征。方法:在这个阶段1的调查中,我们与骨髓增生异常综合征患者18岁或以上或慢性myelomonocytic白血病。合格的受试者被分配到组接受口服剂量的decitabine和cedazuridine升级。起始剂量decitabine 20毫克,cedazuridine 40毫克。治疗周期持续了28天,5天的药品监督管理局。在周期1中,每个病人收到cohort-defined剂量的口服decitabine 3天,1小时静脉输液decitabine 20毫克/米(2)1天,cohort-defined剂量的口服decitabine + cedazuridine在2 - 5天。在周期2,口服decitabine和cedazuridine在1 - 5天给药。的剂量cedazuridine升级第一,decitabine升级一旦CDA cedazuridine接近最大抑制的效果。药物剂量是升级如果意味着decitabine曲线下面积(AUC)口服药物的不到90%,静脉decitabine队列,如果没有dose-limiting毒性观察。 Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range set as the primary endpoint, and established with intravenous decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for decitabine exposure similar to that for intravenous decitabine exposure. This study is registered with ClinicalTrials.gov, number NCT02103478. FINDINGS: Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1-4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 decitabine AUCs (146 ng x h/mL for decitabine 30 mg, and 221 ng x h/mL for decitabine 40 mg) closest to the mean intravenous-decitabine AUC (164 ng x h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]). INTERPRETATION: Oral decitabine plus cedazuridine emulated the pharmacokinetics of intravenous decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous decitabine treatment for 5 days. Further study of decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted. FUNDING: Astex Pharmaceuticals, Inc.

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