贝伐单抗在中国晚期恶性肿瘤受试者中的药动学研究

Pharmacokinetic Study of Recombinant Humanized Bevacizumab in Chinese Subjects with Advanced Malignancies

目的确定中国肿瘤患者静脉滴注重组人类抗血管内皮生长因子单克隆抗体贝伐单抗后的药动学参数。比较中国肿瘤患者与高加索肿瘤患者静脉滴注贝伐单抗的药动学参数。方法本次试验为开放性,3阶段(筛查期,治疗期,随访期)试验。所有受试者根据入组先后依次分配至3个剂量组,分别给予5、10、15mg·kg-1贝伐单抗。每个剂量组均在试验的第1天单剂量静脉滴注贝伐单抗,在随后的20d进行安全性评价。能够耐受第1次静脉滴注的受试者在第22、36、50、64天(5mg.kg-1和10mg·kg-1剂量组),或第22、43、64、85天(15mg·kg-1剂量组)给予相同剂量的贝伐单抗。采用酶联免疫法(ELISA)测定贝伐单抗的血清药物浓度。结果多剂量静脉滴注贝伐单抗(给药间隔为每2周/3周)与其单剂量给药后的药动学参数相似。结论本次试验与在高加索患者中进行的Ⅰ期临床研究观察到的药动学参数相似。

OBJECTIVE To characterize the pharmacokinetic（PK）profile of bevacizumab following Ⅳ administration in Chinese patients,and compare of the PK profile of bevacizumab with that of Caucasian patients enrolled in the phase I study.METHODS An open-label,three-period study（screening,treatment and follow up）was designed.All subjects were assigned to one of the three cohorts（n=12）according their enrollment sequence to receive bevacizumab at dose levels of 5,10 or 15 mg·kg-1.At each dose level,dosing began with a single Ⅳ infusion of bevacizumab on study day 1.Following the initial administration,subjects were monitored for safety for 20 d（screening period）.Subjects who tolerated the initial exposure continued to receive the same dose of bevacizumab IV on day 22,36,50 and 64（5,10 mg·kg-1）and on day 22,43,64 and 85（15 mg·kg-1）.The serum bevacizumab concentration was determined with a validated ELISA assay.RESULTS The pharmacokinetic parameters of bevacizumab after multiple doses,were similar to those after a single dose.CONCLUSION The bevacizumab PK parameters were comparable between Chinese,obtained from this study,and Caucasian,which were obtained from a historical Phase I study.