Dines G D, Bethell R, Daniel M
Glaxo Wellcome Research and Development, Ware, Hertfordshire, England.
Drug Saf. 1998 Sep;19(3):233-41. doi: 10.2165/00002018-199819030-00006.
Developing novel compounds with low toxicity may present more difficulties for pharmaceutical companies than developing compounds with known class-related effects. The absence of clearly identified toxicity may be a consequence either of an inadequate or poorly designed toxicity programme or of the very low toxicity of the novel compound. To enable an informed risk assessment to be undertaken prior to registration, regulatory authorities must satisfy themselves that all efforts to fully evaluate the toxicity profile of a novel compound have been made. Zanamivir is a novel antiviral agent developed for the treatment and prevention of influenza when administered by the oral inhaled route. The toxicology programme for zanamivir was designed to support both a short term treatment indication for patients clinically diagnosed with influenza and a longer term treatment indication for the prevention of influenza. The toxicology studies demonstrated that zanamivir has very low toxicity and no drug-specific toxicities were observed in animal toxicity studies. Systemic plasma concentrations 1336-fold those achieved in clinical use were not associated with significant adverse effects. In the absence of dose-limiting toxicity in animal studies and in an attempt to identify target-organ toxicity, the high dosage level in all repeat dose studies was selected to be the maximum practicable. In the rat, nonspecific effects were seen in the respiratory tract following long term inhaled administration and in the kidneys following continuous infusion. However, these nonspecific effects were consequences of the excessive dosages administered and are not related specifically to zanamivir; thus, they are without relevance to the clinical use of this agent.
对于制药公司而言，研发低毒性的新型化合物可能比研发具有已知类别相关效应的化合物面临更多困难。未明确识别出毒性可能是毒性试验方案设计不当或不充分所致，也可能是新型化合物本身毒性极低的结果。为了在注册前进行明智的风险评估，监管机构必须确保已尽一切努力全面评估新型化合物的毒性特征。扎那米韦是一种新型抗病毒药物，通过口服吸入途径给药，用于治疗和预防流感。扎那米韦的毒理学试验方案旨在支持针对临床诊断为流感的患者的短期治疗适应症以及预防流感的长期治疗适应症。毒理学研究表明，扎那米韦毒性极低，在动物毒性研究中未观察到药物特异性毒性。临床使用中血浆浓度的1336倍的全身血浆浓度与显著不良反应无关。由于在动物研究中未出现剂量限制性毒性，并且为了确定靶器官毒性，所有重复剂量研究中的高剂量水平均选择为最大可行剂量。在大鼠中，长期吸入给药后呼吸道出现非特异性效应，持续输注后肾脏出现非特异性效应。然而，这些非特异性效应是给药剂量过高的结果，并非与扎那米韦有特定关联；因此，它们与该药物的临床使用无关。
