重组人血小板生成素临床耐受性试验

Clinical tolerance test of recombinant human thrombopoietin

目的 评估国产重组人血小板生成素 (rhTPO)在人体内的安全性。观察其对血象、血小板聚集功能等的影响及注射后抗体产生情况。方法 2 7名正常人分为 4组 ,分别单次皮下注射rhTPO 0 2 5、0 5、1 0 μg/kg或 2 0 μg/kg ,5例化疗后急性白血病 ,2例非霍奇金淋巴瘤患者每日皮下注射rhTPO 1 0 μg/kg,连续 7～ 14d ,动态观测血象、血小板聚集、血清生化指标和抗rhTPO抗体等。 结果 2 7名正常人单次皮下注射rhTPO后仅 1例在给药后 6h体温一度至 37 4℃ ;1例给药次日出现轻度乏力、纳差和思睡 ;1例出现一过性丙氨酸转氨酶和天门冬氨酸转氨酶轻度升高。血小板数约于给药后第 14d达高峰 ,与给药前相比 ,平均升高 2 4%～ 5 2 % ,给药后 2 1d基本回落至基础水平。血小板升高时聚集功能无明显改变。 7例血液肿瘤患者接受连续皮下注射rhTPO后未出现与药物相关的不适反应 ;1例出现一过性丙氨酸转氨酶和天门冬氨酸转氨酶轻度升高 ;4例用药后血小板数出现不同程度的升高 ;1例给药后血清中检出一过性低滴度 (1∶5 )抗rhTPO抗体。结论 rhTPO单次皮下注射(0 2 5～ 2 0 μg/kg)和每日 1次皮下注射 (1 0 μg/kg ,7～ 14d)对人体是安全的 ,不良反应轻微。rhTPO具有特异性和剂量依赖性升血小板作用 。

Objective To evaluate the safety of domestic recombinant human thrombopoietin (rhTPO) in human body and the its effects on hemogram and platelet function, and induction of anti rhTPO antibody. Methods In the single dose tolerance test, twenty seven healthy volunteers were randomly divided into 4 groups. rhTPO was injected subcutaneously at the doses of 0.25 μg/kg, 0.5 μg/kg, 1 μg/kg, and 2 μg/kg respectively. In the multiple dose tolerance test, 7 patients with non Hodgkin lymphoma or acute leukemia after chemotherapy received rhTPO at the dose of 1.0 μg/kg for 7～14 days. The symptoms (if any), complete blood count, platelet aggregation test, serum chemistry, and anti rhTPO antibody were followed serially. Results Out of the 27 healthy volunteers receiving single dose of rhTPO, one showed transient increase of body temperature to 37.4℃ six hours after the injection; one felt mild fatigue, anorexia, and somnolence the day after injection, and one showed transient elevation of alanine transminase (ALT) and asparate aminotransferase (AST) levels. Single dose administration of rhTPO at the doses of 0.5 μg/kg, 1.0 μg/kg, and 2.0 μg/kg was associated dose dependently with 24%～52% increase of platelet count, peaking at the day 14 and returning to the baseline Level by day 21. No abnormality was observed in aggregation function when the platelet count peaked. Single dose administration of rhTPO showed no influence on red blood cells and white blood cells. In the multiple dose group, rhTPO at the dose of 1 0 μg·kg -1 ·d -1 for 7～14 days was well tolerated by patients with hemotological malignancies. One patient developed transient slight elevation of serum ALT and AST. After the treatment with rhTPO, platelet counts increased to some extent in 4 patients. Low titer (1∶5) of anti rhTPO antibody was found transiently in one patient. Conclusion A single bolus subcutanenous injection of 0.25～2.0 μg/kg rhTPO and daily subcutaneous injection of 1.0 μg/kg rhTPO for 7～14 days are well tolerated by human beings and without significant adverse effect. rhTPO increases peripheral platelet count and has no effect on aggrgation funtion. Circulating anti rhTPO antibody occurs after multiple administration of rhTPO. However, its clinical significance remains to be studied.