Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers
Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers
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DOI：
10.1089/jir.1996.16.759
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发表时间：
1996-10-01
影响因子：
2.3
通讯作者：
Darragh, A
中科院分区：
文献类型：
--
作者：
Salmon, P;LeCotonnec, JY;Darragh, A
重组人干扰素-β (rHuIFN-β 1a) 的药代动力学和药效学在给予 12 名健康男性志愿者后进行评估。每位受试者以双盲、平衡、随机顺序、交叉顺序接受单剂量 6 MIU 的 rHuIFN-β 1a (Rebif) 静脉注射、肌肉注射和皮下注射。或匹配安慰剂四次，间隔 1 周的清洗期，在预设时间收集血样，用于测量血清 IFN-β 水平和细胞内 2'-5'-寡腺苷酸合成酶水平，定期监测血压、坐心率、呼吸频率、口腔体温和耐受性，所有 rHuIFN-β 1a 给药均耐受良好，尽管约一半受试者如预期出现流感样综合征，静脉注射后推注后，rHuIFN-β 1a 的药代动力学通过经典的二室模型得到了很好的描述，rHuIFN-β 1a 的平均总清除率约为 100 L 。 h(-1)。分布半衰期为 5 分钟，终末半衰期约为 5 小时。或 s.c.注射后，血清 IFN-β 谱相当平坦，大约六分之一的给药剂量可全身吸收。临床和生物学效应的程度和持续时间与给药途径和 IFN-β 血清水平无关，即使当 IFN-β 血清水平恢复至基线并且单次给药后 3 天仍显着升高，生物药效效应仍然持续。在主要寻求免疫调节作用的适应症中，优选给药途径，主要通过静脉注射增强抗病毒和抗增殖活性。尽管其应用在实践中受到限制，但在病理部位提供足够药物水平的途径。
The pharmacokinetics and pharmacodynamics of recombinant human interferon-beta (rHuIFN-beta 1a) were assessed following administration to 12 healthy male volunteers, Each subject received, in a double-blind, balanced, random-order, crossover sequence, single doses of 6 MIU of rHuIFN-beta 1a (Rebif) i.v., i.m., and s.c. or matching placebo on four occasions separated by washout periods of 1 week, Blood samples were collected at preset times for the measurement of serum IFN-beta levels and of intracellular 2'-5'-oligoadenylate synthetase levels, Blood pressure, sitting heart rate, respiratory rate, oral body temperature, and tolerance were monitored regularly, All administrations of rHuIFN-beta 1a were well tolerated, although about half of the subjects had a flu-like syndrome, as expected, After i.v. bolus injection, the pharmacokinetics of rHuIFN-beta 1a were well described by a classic two-compartment model, Mean total clearance of rHuIFN-beta 1a was about 100 L . h(-1). The distribution half-life was 5 min, and the terminal half-life was approximately 5 h, After i.m. or s.c. injection, serum IFN-beta profiles were rather flat, and about one sixth of the administered dose was available systemically. Extent and duration of clinical and biologic effects were independent of the route of administration and of the IFN-beta serum levels, Biologic pharmacodynamic effects persisted even when IFN-beta serum levels had returned to baseline and were still significantly elevated 3 days after a single dose, Because of the independence of the extent and duration of clinical and biologic pharmacodynamic effects from the route of administration and from the IFN-beta serum levels, the s.c. route of administration is preferred in indications in which primarily an immunomodulatory action is sought, Predominantly antiviral and antiproliferative activity is enhanced by the i.v. route to provide adequate drug levels at the site of pathology, although its application is limited on practical grounds.