肝损伤的药物动力学的影响nilotinib:一个非盲、单剂,与这些相应平行的组织学习。

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阴OQ,加拉格尔N,田中C,费舍尔D, Sethuraman V,周W,林,Heuman D, Schran H

肝损伤的药物动力学的影响nilotinib:一个非盲、单剂,与这些相应平行的组织学习。

其他。2009;31 Pt 2:2459 - 69。doi: 10.1016 / j.clinthera.2009.11.015。

PubMed ID

20110053 (在PubMed

]

文摘

背景:Nilotinib是第二代bcr - abl酪氨酸激酶抑制剂批准imatinib-resistant费城染色体阳性病人的治疗慢性粒细胞白血病的长期或加速阶段或无法容忍伊马替尼。Nilotinib是肝脏通过氧化和羟基化代谢途径,主要由细胞色素P450 3 a4同工酶介导。Interpatient可变性在系统性接触nilotinib报从32%到64%不等。目的:本研究比较了药物动力学nilotinib与肝损伤和主题的主题与正常肝的功能。方法:肝损伤分为轻度(儿童年级)、中度(儿童年级B),或严重(儿童年级C)。健康的对照组与hepatically受损对象的年龄(+ / -10年)和体重(+ / - -20%)。所有受试者接受单剂量口服200毫克nilotinib在禁食条件下,和系列收集血液样本在特定的时间给药后120小时。血清nilotinib浓度测量使用验证质/ MS分析与量化的下限2.5 ng / mL。药代动力学参数分析了C (max)、T (max), AUC (0-last), AUC (0-infinity)、T (1/2), CL / F和Vz / F。耐受性评估包括不良事件(AEs),定期监测临床实验室的措施(如血液学、血液化学、尿液),身体检查,生命体征,ecg。每个AE评估的临床意义,严重程度,持续时间,与研究药物,并采取行动。 RESULTS: The study enrolled 18 subjects with hepatic impairment (all male; age range, 47-67 years; weight range, 73.9-103.9 kg) and 9 healthy controls (all male; age range, 36-62 years; weight range, 73.3-109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC(0-infinity) was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t(1/2) was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in Vz/F in the latter 2 groups. All AEs were mild or moderate, and the frequency of AEs was not associated with the degree of hepatic impairment. AEs included abdominal pain (1 subject with mild impairment), dyspepsia (2 with mild impairment), flatulence (1 with severe impairment), nausea (1 with mild impairment), urinary tract infection (1 with mild impairment), back pain (1 each with mild impairment and severe impairment, 1 control subject), and headache (1 each with mild impairment and severe impairment). CONCLUSIONS: After a single 200-mg dose, nilotinib pharmacokinetics were modestly affected by hepatic impairment. The extent of change in nilotinib exposure in subjects with hepatic impairment was generally within the range of variability that has been observed clinically. The results of this study suggest that dose adjustment may not be necessary in patients with hepatic impairment. Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
Nilotinib	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 抑制剂	细节