重组人淋巴毒素-α衍生物静脉注射的临床药代动力学试验

[Clinical pharmacokinetic trial of intravenous injection of recombinant human lymphotoxin-alpha derivative].

作者信息

Li Su, Wang Feng-Hua, Liao Hai, Li Yu-Hong, Jiang Wen-Qi, Guan Zhong-Zhen

机构信息

State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, P. R. China.

出版信息

Ai Zheng. 2006 Dec;25(12):1524-8.

PMID:17166379

Abstract

BACKGROUND & OBJECTIVE: Animal experiment showed that recombinant human lymphotoxin-alpha derivate (rhLTalpha-Da) could inhibit tumor growth,activate immunity, sensitize tumors to chemotherapy, and has low toxicity in vivo. rhLTalpha-Da won't accumulate after multiple administrations. This study was to investigate pharmacokinetic profile of rhLTalpha-Da in tumor patients to provide reference for phase II clinical trail.

METHODS

The dosage of rhLTalpha-Da was 10, 20, and 33 microg x m(-2) x d(-1) according to phase I clinical endurance trial. rhLTalpha-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 rhLTalpha-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%. rhLTalpha-Da in pharmacokinetics 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 microg x m(-2) x d(-1) and 20 microg x m(-2) x d(-1) of rhLTalpha-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 x m(-2) x h(-1) and (269.60+/-24.52)ng x m(-2) x h(-1); the areas under concentration-time curve (AUC) were (74.6+/-18.4) ng x h x L(-1) and (99.0+/-17.8) ng x h x L(-1), respectively.

CONCLUSIONS

The pharmacokinetics of rhLTalpha-Da after infusion is fitted to one compartment model and its elimination is linear. There is no rhLTalpha-Da accumulation after multiple administrations.

摘要

背景与目的

动物实验表明，重组人淋巴毒素-α衍生物（rhLTα-Da）可抑制肿瘤生长、激活免疫、使肿瘤对化疗敏感，且体内毒性较低。多次给药后rhLTα-Da不会蓄积。本研究旨在探讨rhLTα-Da在肿瘤患者中的药代动力学特征，为Ⅱ期临床试验提供参考。

方法

根据Ⅰ期临床耐受性试验，rhLTα-Da的剂量为10、20和33μg·m⁻²·d⁻¹。将rhLTα-Da与100ml 5%葡萄糖溶液混合，然后在连续5天的每天30分钟内输注完毕。在输注前后的不同时间点采集血样和尿样。采用酶联免疫吸附测定法（ELISA）和荧光微球免疫测定法（FBI）检测血样和尿样中rhLTα-Da的浓度。通过3p97药代动力学程序计算主要药代动力学参数。

结果

2003年2月至2003年12月，共纳入19例患者。ELISA法的线性范围、特异性、精密度、准确度和稳定性均符合要求。定量下限（LLOQ）为39pg/ml。FBI法的线性范围、灵敏度、特异性、批内精密度和准确度均符合要求，但批间精密度变异系数超过20%。rhLTα-Da的药代动力学符合一室开放模型：其从血清中快速消除，输注停止后2小时无法检测到。rhLTα-Da剂量为33μg·m⁻²·d⁻¹和20μg·m⁻²·d⁻¹时的半衰期（t1/2）分别为（0.24±0.09）小时和（0.25±0.10）小时；分布容积（Vd）分别为（35.8±1.6）L/m²和（43.3±26.0）L/m²；清除率（CL）分别为（343.36±63.23）ng·m⁻²·h⁻¹和（269.60±24.52）ng·m⁻²·h⁻¹；浓度-时间曲线下面积（AUC）分别为（74.6±18.4）ng·h·L⁻¹和（99.0±17.8）ng·h·L⁻¹。