注射用重组人淋巴毒素α衍生物的临床药代动力学研究

Clinical Pharmacokinetic Trial of Intravenous Injection of Recombinant Human Lymphotoxin-α Derivative

背景与目的:动物实验研究表明重组人淋巴毒素α衍生物(recombinanthumanlymphotoxin-αderivative,rhLTα-Da)具有良好的抗肿瘤、免疫激活和化疗增敏作用,且毒性较低,连续给药在动物体内不蓄积。本研究目的是考察rhLTα-Da在肿瘤患者体内的药代动力学行为,为Ⅱ期临床安全合理用药提供理论依据。方法:根据耐受性试验确定rhLTα-Da人体药代动力学试验低、中、高剂量级分别为10、20、33μg·m-2·d-1。将rhLTα-Da溶于100ml5%葡萄糖注射液,静脉恒速滴注0.5h,连续5天给药。于给药前、给药后不同时间收集血标本和尿标本。分别采用酶联免疫吸附测定法(enzyme-linkedimmunosorbentassay,ELISA)和荧光磁珠免疫分析法(fluorescencebeadimmunoassay,FBI)测定患者给药后血清和尿液中rhLTα-Da浓度。用3p97软件拟合rhLTα-Da体内模型,描绘rhLTα-Da血药浓度-时间曲线,并计算药代动学参数。结果:入组的19例患者中,ELISA法的线性范围、特异性、准确度和精确度满足药代动力学要求,定量下限值为39pg/ml。FBI法的线性、线性范围、定量下限、准确度、特异性符合药代动力学研究,日间变异系数大于20%。rhLTα-Da进入体内后呈一室模型,迅速从血清中清除,给药停止即刻的浓度最高,2h后血清中的rhLTα-Da浓度已低于检测限。20μg·m-2·d-1和33μg·m-2·d-1剂量级药代动力学参数结果:半衰期分别为(0.24±0.09)h和(0.25±0.10)h,表观分布容积分别为(35.8±1.6)L/m2和(43.3±26.0)L/m2,清除率分别为(343.36±63.23)ng·m-2·h-1和(269.60±24.52)ng·m-2·h-1;血药浓度-时间曲线下面积分别为(74.6±18.4)ng·h·L-1和(99.0±17.8)ng·h·L-1。结论:在研究剂量范围内rhLTα-Da血药浓度-时间曲线符合一室模型,消除遵循一级动力学,连续5天给药不蓄积。

BACKGROUND ＆ OBJECTIVE： Animal experiment showed that recombinant human lymphotoxin-α derivate （rhLTα-Da） could inhibit tumor growth ,activate immunity, sensitize tumors to chemotherapy, and has low toxicity in vivo. rhLTα-Da won＇t accumulate after multiple administrations. This study was to investigate pharmacokinetic profile of rhLTα-Da in tumor patients to provide reference for phase II clinical trail. METHODS： The dosage of rhLTα-Da was 10, 20, and 33μg·m^-2·d^-1 according to phase I clinical endurance trial, rhLTα-Da was mixed with 100 ml 5% glucose solution, and then infused over 30 min on each of 5 consecutive days. Blood samples and urine samples were collected before and after infusion at different time points. Enzyme-linked immunosorbent assay （ELISA） and fluorescent bead immunoassay （FBI） were used to detect the concentration of rhLTα-Da in blood and urine. The main pharmacokinetic parameters were calculated by 3p97 pharmacokinetic program. RESULTS：From Feb. 2003 to Dec. 2003, 19 patients were enrolled. The linear range, specificity, precision, accuracy, and stability of ELISA method were satisfied. The lower limit of quantification （LLOQ） was 39 pg/ml. The linear range, sensitivity, specificity, intra-assay precision, and accuracy of FBI method were satisfied, but coefficient of variation of inter-assay precision was over 20%. rhLTα-Da in pharmacikinetics conformed to be a one-compartment open model：it had been eliminated quickly from serum and could not be detected 2 h after the cessation of infusion. The half lives （t1/2） of 33 μg·m^-2·d^-1 and 20 μg·m^-2·d^-1 of rhLTα-Da were （0.24±0.09） h and （0.25±0.10） h; the abundant volumes of distribution （Vd） were （35.8±1.6） L/m^2 and （43.3±26.0） L/m^2;the clearance （CL） were （343.36±63.23） ng·m^-2·h^-1 and （269.60±24.52）ng·m^-2·h^-1;the areas under concentration-time curve （AUC） were （74.6±18.4） ng·h·L^-1 and （99.0± 17.8） ng·h·L^-1, respectively. CONCLUSIONS ： The pharmacokinetics of rhLTα-Da after infusion is fitted to one compartment modle and its elimination is linear. There is no rhLTα-Da accumulation after multiple administrations.