Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-α fusion protein in cynomolgus monkeys
Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-α fusion protein in cynomolgus monkeys
复制标题
DOI：
10.1124/jpet.102.037002
复制
发表时间：
2002-11-01
影响因子：
3.5
通讯作者：
Sung, C
中科院分区：
文献类型：
--
作者：
Osborn, BL;Olsen, HS;Sung, C
干扰素-α被用于治疗某些病毒感染，包括乙肝和丙型肝炎，以及黑色素瘤等癌症。未经修饰的干扰素-α的循环半衰期很短，因此有必要在较长时间(6-12个月或更长时间)内频繁给药(每天或每周三次)。为了改善干扰素-α的药代动力学，降低给药频率，将干扰素-α与人血清白蛋白融合，产生一种新的蛋白质Albuferon。在体外比较阿尔布费隆和干扰素-α显示出相似的抗病毒和抗增殖活性，尽管在摩尔基础上阿尔布费隆的效力不如干扰素-α。融合蛋白在猴子体内的药代动力学和药效学特性得到增强。单次静脉注射(30 mg/kg)后，表观清除量(清除量除以生物利用度)为1.4ml/h/kg，终末半衰期为93h，生物利用度为%。在其他猴子研究中，阿尔布费隆的清除速度比其他猴子皮下途径给出的干扰素-α慢约140倍，半衰期长18倍。根据体外生物测定，来自Albuferon处理的猴子的血清在大于或等于8天的时间内表现出剂量相关的抗病毒活性，而来自干扰素-α处理的动物的抗病毒活性在第0天仅略高于赋形剂。皮下给药后，相对于干扰素-α或赋形剂治疗的动物，2‘，5’-寡腺苷合成酶mRNA的显著增加保持在大于或等于10天。Albuferon的药代动力学改善伴随着药效学反应的改善，这表明Albuferon可能提供了与干扰素-α相比减少给药频率和潜在改善疗效的好处。
Interferon-alpha (IFN-alpha) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-alpha makes frequent dosing (daily or three times weekly) over an extended period (6-12 months or more) necessary. To improve the pharmacokinetics of IFN-alpha and decrease dosing frequency, IFN-alpha was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-alpha showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-alpha. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 mug/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 mug/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-alpha given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated dose-related antiviral activity for greater than or equal to8 days based on an in vitro bioassay, whereas antiviral activity from IFN-alpha-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2',5'-oligoadenylate synthetase mRNA relative to IFN-alpha- or vehicle-treated animals were maintained for greater than or equal to10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-alpha.