重组人肿瘤坏死因子DK2Ⅰ期临床试验

PhaseⅠClinical Trial of Recombinant Human Tumor Necrosis Fac-tor-Alpha DK2(Rhtnfα-DK2)

[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。

To determine the dose tolerance of recombinant human tumor necrosis factor-alpha DK2(rhTNFα-DK2)and to determine it’s pharmacokinetics paramete.(1)The patients were given rhTNFα-DK2in doses range from300,000U/m 2 to2,000,000U/m 2 (ie.300,000U/m 2 ,600,000U/m 2 ,900,000U/m 2 ,1200,000U/m 2 ,1500,000U/m 2 and2000,000U/m 2 )by i.v.bolus injections(the drugs dissolved in250ml saline)two hours per day,for seven days.(2)With i.v.bolus administration,patient’s serum concentration of rhTNFα-DK2were detected by enzyme-linked immunosorbent assay at0,30,60,65,75,90,105,120,150and180minutes following rhTNFα-DK2injection at dose of2,000,000U/m 2 .Twenty-six patients with malig-nant tumor were enrolled into this study,while2cases were excluded.Eighteen cases were divided to six groups and every group received one of the serial of rhTNFα-DK2treatment.The major side effects were chills,fever,disorder of blood pressure,neutropenia ostalgia and myalgia.None withⅢ/Ⅳdegree side effects were founded.Serum drug concentration was measured in six cases.The distribution in serum matched the one-atrium-ventricle model(t 1/2 value10.1~30.7min,average21.5±7.1min,Vd value35.6~58.2L,average46.5±9.8L).[Conclusion]The dose range of rhTNFα-DK2from300,000U/m 2 to2,000,000U/m 2 are all tolera-ble and no dose-limited toxicity appears.The dose of2,000,000U/m 2 is recommended to phaseⅡclinical study.The distribution in serum accord with the one-atrium-ventricle model(t 1/2 =21.5±7.1min,Vd=46.5±9.8L).