Liu Chang-Ning, Mathialagan Nagappan, Lappin Patrick, Fortner Jay, Somps Chris, Seitis Gary, Johnson Theodore R, Hu Wenyue, Matsumoto Diane
*Investigative Toxicology, Drug Safety R&D, Pfizer Inc., Groton 06340, Connecticut, Drug Safety R&D, Pfizer Inc., San Diego, CA 92121, Comparative Medicine, Pfizer Inc., Groton 06340, Connecticut and Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., San Diego, CA 92121
*Investigative Toxicology, Drug Safety R&D, Pfizer Inc., Groton 06340, Connecticut, Drug Safety R&D, Pfizer Inc., San Diego, CA 92121, Comparative Medicine, Pfizer Inc., Groton 06340, Connecticut and Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., San Diego, CA 92121.
Toxicol Sci. 2015 Jan;143(1):116-25. doi: 10.1093/toxsci/kfu213. Epub 2014 Oct 16.
Crizotinib (Xalkori) is a tyrosine kinase inhibitor of both anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (c-Met). Though not predicted from standard nonclinical toxicological evaluation, visual disturbance became a frequently observed adverse event in humans. To understand the possible mechanism of this vision effect, an in vivo electroretinogram (ERG) study was conducted to assess retinal functional changes following oral administration of crizotinib. Immunohistochemical (IHC) staining of ALK and c-Met in the neural retinas of human, non-human primate, dog, rat, and mouse was used to aid in the animal model selection. ALK IHC staining was identified predominantly in the ganglion cell and inner nuclear layers of most species evaluated, in the inner plexiform layer in human and rodent, and in the nerve fiber layer in human and rat only. There was no apparent staining of any layer of the neural retina for c-Met in any of the species evaluated. ERG measurements identified a significant reduction in b-wave amplitude during the initial phase of dark adaptation in the crizotinib-treated rats. ERGs were also taken following oral administration of PF-06463922 (an ALK-selective inhibitor), for an understanding of potential kinase involvement. ERG effects were not observed in PF-06463922-treated animals when comparable exposures in the vitreous humor were achieved. Collectively, our results suggest that the ERG b-wave amplitude decreases during dark adaption following crizotinib administration may be related to signaling changes within the retina in rats, likely independent of ALK inhibition.
克唑替尼（赛可瑞）是一种间变性淋巴瘤激酶（ALK）和间质上皮转化因子（c-Met）的酪氨酸激酶抑制剂。尽管标准的非临床毒理学评估未预测到，但视觉障碍在人类中成为一种常见的不良事件。为了解这种视觉效应的可能机制，进行了一项体内视网膜电图（ERG）研究，以评估口服克唑替尼后视网膜功能的变化。使用免疫组织化学（IHC）染色检测人、非人灵长类动物、狗、大鼠和小鼠神经视网膜中的ALK和c-Met，以辅助动物模型的选择。在大多数评估物种的神经节细胞层和内核层中主要鉴定到ALK IHC染色，在人和啮齿动物的内网状层中以及仅在人和大鼠的神经纤维层中也有染色。在任何评估物种中，神经视网膜的任何层均未观察到c-Met的明显染色。ERG测量发现，在克唑替尼治疗的大鼠中，暗适应初始阶段b波振幅显著降低。口服PF-06463922（一种ALK选择性抑制剂）后也进行了ERG测量，以了解潜在的激酶参与情况。当在玻璃体液中达到可比暴露量时，PF-06463922治疗的动物未观察到ERG效应。总体而言，我们的结果表明，克唑替尼给药后暗适应期间ERG b波振幅降低可能与大鼠视网膜内的信号变化有关，可能与ALK抑制无关。
