de Zafra Christina L Zuch, Sasseville Vito G, Matsumoto Steven, Freichel Christian, Milton Mark, MacLachlan Timothy K, Farman Cindy, Raymond Iona, Gupta Swati, Newton Ronald, Atzpodien Elke-Astrid, Thackaberry Evan A
Safety Assessment, Genentech, Inc., South San Francisco, CA, United States.
Preclinical Safety, Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Regul Toxicol Pharmacol. 2017 Jun;86:221-230. doi: 10.1016/j.yrtph.2017.03.013. Epub 2017 Mar 16.
The nonclinical safety evaluation of therapeutic drug candidates is commonly conducted in two species (rodent and non-rodent) in keeping with international health authority guidance. Biologic drugs typically have restricted species cross-reactivity, necessitating the evaluation of safety in non-human primates and thus limiting the utility of lower order species. Safety studies of cross-reactive ocular biologic drug candidates have been conducted in rabbits as a second toxicology species, despite the fact that rabbits are not a rodent species. Such studies are often confounded by the development of anti-drug antibodies and severe ocular inflammation, the latter requiring studies to be terminated prematurely for animal welfare reasons. Notably, these confounding factors preclude the interpretation of safety. Nonclinical toxicology programs should be designed with consideration of ethical animal use and 3Rs principles (Replacement, Reduction and Refinement). The experience of several pharmaceutical sponsors, demonstrating that toxicology studies of ocular (intravitreal and topical ocular) biologic drug candidates in the rabbit are of limited interpretive value, calls into question the utility of such studies in this species and indicates that such studies should not be conducted.
按照国际卫生当局的指导原则，治疗性候选药物的非临床安全性评估通常在两个物种（啮齿类和非啮齿类）中进行。生物药物通常具有有限的物种交叉反应性，因此需要在非人灵长类动物中评估安全性，从而限制了低等物种的实用性。尽管兔子不是啮齿类动物，但作为第二种毒理学物种，已在兔子中对具有交叉反应性的眼部生物候选药物进行了安全性研究。此类研究常常因抗药物抗体的产生和严重的眼部炎症而受到干扰，后者出于动物福利原因需要提前终止研究。值得注意的是，这些混杂因素妨碍了对安全性的解释。非临床毒理学计划的设计应考虑动物的人道使用和3R原则（替代、减少和优化）。几家制药公司的经验表明，在兔子中对眼部（玻璃体内和局部眼部）生物候选药物进行的毒理学研究的解释价值有限，这对该物种此类研究的实用性提出了质疑，并表明不应进行此类研究。
