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[目的]研究人体对重组人肿瘤坏死因子DK2(rhTNFα鄄DK2)的耐受剂量,测定其在人体内的药代动力学参数。[方法](1)rhTNFα鄄DK2按30万、60万、90万、120万、150万和200万U/m26个剂量组渐次递增,每组3例。药物溶于250ml生理盐水中静滴2h,连用7天。(2)至200万U/m2剂量组时,rhTNFα鄄DK2200万U/m2溶于250ml生理盐水中匀速静滴1h,分别在0、30、60、65、75、90、105、120、150和180min取静脉血2ml,采用酶联免疫法(ELISA)测定血药浓度。[结果]26例恶性肿瘤患者入组,2例出组;18例按顺序分6组完成耐受性试验主要不良反应是寒战、发热、血压异常、白细胞降低和骨肌肉酸痛,未出现Ⅲ度不良反应;200万U/(m2·d)被确认为安全剂量。6例接受血药浓度测定:rhTNFα鄄DK2在体内呈一房室模型,t1/2(10.1～30.7)min,平均值(21.5±7.1)min,Vd(35.6～58.2)L,平均值(46.5±9.8)L。[结论]rhTNFα鄄DK2(30～200)万U/(m2·d)连用7天,未出现剂量限制性毒性,Ⅱ期临床试验的推荐剂量为200万U/(m2·d)。rhTNFα鄄DK2在体内呈一房室模型,t1/2=21.5min,Vd=46.5L。
[Objective] To study the tolerance dose of recombinant human tumor necrosis factor DK2 (rhTNFα-DK2) and to determine its pharmacokinetic parameters in human. [Method] (1) rhTNFα-DK2 was gradually increased by 30, 600, 900, 1200, 1500 and 200 000 U / m26 doses, with 3 in each group. Drugs dissolved in 250ml saline intravenously 2h, once every 7 days. (2) to 2000000 U / m2 dose group, rhTNFα-DK2200 million U / m2 dissolved in 250ml normal saline intravenous infusion 1h, respectively, at 0,30,60,65,75,90,105,120,150 And 180min to take venous blood 2ml, using enzyme-linked immunosorbent assay (ELISA) determination of plasma concentration. [Results] Twenty-six patients with malignant tumor were enrolled in the study and two patients were enrolled in the study. 18 patients completed the tolerance test in order of 6 groups. The main adverse reactions were chills, fever, abnormal blood pressure, leukopenia and sore muscle. Adverse reactions; 2 million U / (m2 · d) were confirmed as safe dose. Six patients received blood concentration determination: rhTNFα-DK2 showed a one-compartment model in vivo with t1 / 2 (10.1-30.7) min, mean (21.5 ± 7.1) min, Vd (35.6-58.2) L, ± 9.8) L. [Conclusion] The dosage of rhTNFα-DK2 (30-200) U / (m2 · d) for 7 days does not appear dose-limiting toxicity, and the recommended dose of Phase Ⅱ clinical trial is 2 million U / (m2 · d). rhTNFα-DK2 in the body was a one-compartment model, t1 / 2 = 21.5min, Vd = 46.5L.