注射用重组人肿瘤坏死因子受体突变体-Fc融合蛋白对中国健康志愿者血浆中肿瘤坏死因子-α浓度水平的影响

Effects of recombinant fusion protein of human tumor necrosis factor receptor mutant and Fc fragment for injection on the plasma concentration of tumor necrosis factor-α in Chinese healthy volunteers

目的研究不同剂量重组人肿瘤坏死因子受体突变体-Fc融合蛋白[rhTNFR(m):Fc]单次皮下给药对中国健康志愿者血浆中肿瘤坏死因子-α(TNF-α)表达水平的影响。方法研究纳入56例健康成年志愿者,分为6个剂量组,分别腹部皮下注射rhTNFR(m):Fc 10,20,35,50,65,75 mg,测定给药前(0 h),给药后4,48,96,168,216,264,312,384,480 h的血浆中游离TNF-α和总TNF-α的浓度。结果单次给药0~264 h后,各个剂量组志愿者体内游离TNF-α和总TNF-α浓度均出现了显著升高;在给药264~480 h后,血浆中游离TNF-α和总TNF-α浓度逐渐下降;给药后480 h,游离TNF-α浓度几乎降至正常。在10~75 mg剂量内,血浆中游离TNF-α和总TNF-α在体内的暴露量(Cmax)与rhTNFR(m):Fc的剂量之间无明显的线性相关性。结论中国健康志愿者单次给予rhTNFR(m):Fc后,可引起血浆中游离TNF-α和总TNF-α水平的升高,因此,血浆中游离TNF-α和总TNF-α水平可能并不适合作为该类药物的药效学评价指标。

Objective To access the effects of different doses of recombinant fusion protein of human tumor necrosis factor receptor mutant and Fc fragment [rhTNFR（ m） ： Fc] after a single subcutaneous injection on the plasma concentration of tumor necrosis factor-α（ TNF-α） in Chinese healthy volunteers. Methods A total of 56 healthy Chinese volunteers were randomly divided into 6 groups to receive a single injection of 10,20,35,65,75 mg of rhTNFR（ m） ： Fc. The plasma concentrations of TNF-α and total TNF-α were determined at 1 h pre-dose and at 4,48,96,168,216,264,312,384,480 h post-dose.Results After administration of rhTNFR（ m） ： Fc at 0-264 h,the plasma concentrations of free TNF-α and total TNF-α increased significantly in the each group. At 264-480 h post-dose,the concentration of them began to decrease, and at 480 h the concentration of free TNF-α almostly decreased to normal levels. In the dose range of10-75 mg,the exposure of free TNF-α and total TNF-α（ Cmax） had no significant correlation with the dose of rhTNFR（ m） ： Fc. Conclusion After giving the single dose of rhTNFR（ m） ： Fc,there was an increase of free and total TNF-α plasma concentration in Chinese healthy volunteers. As a result,the plasma concentration of free and total TNF-α may not be a suitable pharmacodynamic evaluation index.