仿制与原研瑞戈非尼片安全性比较的Ⅰ期临床试验

Phase I clinical trial of safety comparison between the generic and the original regorafenib tablets

目的比较仿制与原研瑞戈非尼片的安全性。方法空腹状态下单剂给药的健康男性人体生物等效性试验(空腹试验)和低脂餐后状态下单剂给药的健康男性人体生物等效性试验(餐后试验)均为单中心、随机、开放、2周期、自身交叉设计的Ⅰ期临床试验。受试制剂为北京双鹭药业股份有限公司生产的瑞戈非尼片,参比制剂为拜耳医药保健有限公司生产的瑞戈非尼片。2项试验中男性健康受试者均随机分为2组,每组均服药2个周期,但服用受试制剂(T)和参比制剂(R)的顺序不同,分别为T⁃R和R⁃T组。受试者分别在试验第1、13天空腹或低脂餐后服用受试或参比制剂1片(40 mg)。服药后定期行生命体征、心电图、全身体检和血尿常规、血生化、凝血功能等检查,记录不良事件(AE)的发生情况并进行AE严重程度分级。结果空腹试验纳入受试者64例,T⁃R组和R⁃T组各32例,受试和参比制剂各获得61和57例受试者的安全性数据;餐后试验纳入受试者76例,T⁃R组和R⁃T组各38例,受试和参比制剂各获得74例受试者的安全性数据。空腹试验和餐后试验中,服用受试制剂者AE发生率与服用参比制剂者比较,差异均无统计学意义[41.0%(25/61)比31.6%(18/57),χ^(2)=1.125,P=0.289;56.8%(42/74)比45.9%(34/74),χ^(2)=0.183,P=0.188]。2项试验中共发生230例次AE,其中1级228例次(99.1%,受试制剂131例次,参比制剂97例次),2级2例次(0.9%,受试制剂、参比制剂各1例次),无≥3级AE发生。2项试验中AE表现类型一致,最为常见者均为心动过缓,其次为心电图QT间期延长。心电图异常均为例行检查时发现,受试者无明显临床症状。结论仿制与原研瑞戈非尼片在空腹和餐后状态下单剂服用后的安全性一致。

Objective To compare the safety of the generic and the original regorafenib tablets.Methods Two single center,randomized,open⁃label,2⁃period self⁃crossover phase I clinical trials(single dose)were conducted under fasting condition and with low⁃fat meal respectively in healthy adult volunteers.The test preparation(T)of regorafenib was produced by Beijing Sl Pharmaceutical Co.,Ltd.and the reference preparation(R)was produced by Bayer HealthCare Pharmaceuticals Inc.In the 2 trials,male healthy subjects were randomly divided into 2 groups,respectively,and took 2 times of the preparations with different order in each group,which were R⁃T group(subjects took R on day 1 and then T on day 13)and T⁃R group(subjects took T on day 1 and then R on day 13).The subjects took drugs under fasting condition and with low⁃fat meal in the 2 trials respectively.After medication,vital signs detection,electrocardiogram,general physical examination,blood routine,blood biochemical,coagulation function,and other tests were performed regularly,and the occurrence of adverse events(AEs)were recorded and the severity of AEs was assessed.Results Sixty⁃four subjects were enrolled in the trial under fasting condition,including 32 in the T⁃R group and 32 in the R⁃T group,and the safety data was obtained from 61 and 57 subjects taking T and R,respectively.Seventy⁃six subjects were included in the postprandial trial,including 38 in the T⁃R group and 38 in the R⁃T group,and the safety data was obtained from 74 subjects taking T and R,respectively.In the 2 trials,there was no significant difference in the incidence of AEs between subjects taking T and those taking R[41.0%(25/61)vs.31.6%(18/57),χ^(2)=1.125,P=0.289;56.8%(42/74)vs.45.9%(34/74),χ^(2)=0.183,P=0.188].A total of 230 AEs occurred in the 2 trials,of which 228 cases were grade 1(99.1%,131 and 97 AEs occurred in subjects taking T and R,respectively),2 cases were grade 2(0.9%,1 AE occurred in subjects taking T and R,respectively),and no grade≥3 AEs occurred.The types of AEs occurred in the 2 trials were the same,of which bradycardia was the most common,followed by prolonged QT interval of ECG.All ECG abnormalities were found during routine examinations,and no subjects had obvious clinical symptoms.Conclusion The safety of the generic and the original regorafenib tablets was consistent after a single dose administration under fasting condition and with low⁃fat meal.