Salmon P, Le Cotonnec J Y, Galazka A, Abdul-Ahad A, Darragh A
National Drugs Advisory Board, Dublin, Ireland.
J Interferon Cytokine Res. 1996 Oct;16(10):759-64. doi: 10.1089/jir.1996.16.759.
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.
在12名健康男性志愿者给药后，对重组人干扰素-β（rHuIFN-β 1a）的药代动力学和药效学进行了评估。每位受试者按照双盲、均衡、随机顺序、交叉序列，在四个不同时间接受6 MIU的rHuIFN-β 1a（Rebif）静脉注射、肌肉注射和皮下注射单剂量，或匹配的安慰剂，每次给药间隔1周的洗脱期。在预设时间采集血样，用于测定血清干扰素-β水平和细胞内2'-5'-寡腺苷酸合成酶水平。定期监测血压、静息心率、呼吸频率、口腔体温和耐受性。尽管约一半受试者出现了预期的流感样综合征，但所有rHuIFN-β 1a给药均耐受性良好。静脉推注后，rHuIFN-β 1a的药代动力学可用经典的二室模型很好地描述。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。肌肉注射或皮下注射后，血清干扰素-β曲线较为平缓，约六分之一的给药剂量可全身利用。临床和生物学效应的程度和持续时间与给药途径和干扰素-β血清水平无关。即使干扰素-β血清水平已恢复至基线，生物学药效学效应仍持续存在，且在单剂量给药3天后仍显著升高。由于临床和生物学药效学效应的程度和持续时间与给药途径和干扰素-β血清水平无关，在主要寻求免疫调节作用的适应症中，优选皮下给药途径。静脉给药途径可增强主要的抗病毒和抗增殖活性，以在病理部位提供足够的药物水平，尽管基于实际原因其应用受到限制。
