García-García Idrian, González-Delgado Carlos A, Valenzuela-Silva Carmen M, Díaz-Machado Alina, Cruz-Díaz Marisol, Nodarse-Cuní Hugo, Pérez-Pérez Orlando, Bermúdez-Badell Cimara H, Ferrero-Bibilonia Joel, Páez-Meireles Rolando, Bello-Rivero Iraldo, Castro-Odio Fidel R, López-Saura Pedro A
Clinical Trials Division, Center for Biological Research, Havana, Cuba.
BMC Pharmacol. 2010 Nov 23;10:15. doi: 10.1186/1471-2210-10-15.
Interferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers.
A randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria.
The pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h(-1); mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild.
Both formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.
干扰素（IFN）α与聚乙二醇（PEG）结合可产生更好的药代动力学特征和疗效。本研究的目的是在健康男性志愿者中比较一种新的、本地研发的40 kDa聚乙二醇干扰素α-2b制剂与一种参比的市售聚乙二醇干扰素α-2a的药代动力学、药效学和安全性特征。
进行了一项随机、交叉、双盲研究，洗脱期为3周。两组均皮下注射单次180微克聚乙二醇干扰素α-2剂量。纳入了16名表面健康的男性受试者。通过酶免疫测定法（EIA）在336小时内测定血清聚乙二醇干扰素浓度。其他临床和实验室变量用作药效学和安全性标准。
通过EIA进行的药代动力学比较显示两种制剂之间高度相似。尽管个体差异较大，但参数均值非常接近（所有情况下p>0.05）：曲线下面积（AUC）：53623对44311 pg·h/mL；最大浓度（Cmax）：333对271 pg/mL；达峰时间（Tmax）：54对55小时；半衰期（t1/2）：72.4对64.8小时；终末消除率（lambda）：0.011对0.014 h-1；平均驻留时间（MRT）：参比制剂和研究制剂分别为135对123小时。药效学变量也无显著差异：血清新蝶呤和β-2微球蛋白水平、2',5'-寡腺苷酸合成酶表达的刺激以及血清IFN抗病毒活性。观察到药代动力学和药效学浓度-时间曲线之间存在很强的Spearman等级相关性（p<0.01）。两种产品导致的白细胞计数减少相似，安全性特征相似。最常见的不良反应是白细胞减少、发热、血小板减少、转氨酶升高和乏力，大多为轻度。
两种制剂在药代动力学、药效学和安全性方面完全可比。可进行疗效试验以确认临床相似性。
