Crizotinib Reduces the Rate of Dark Adaptation in the Rat Retina Independent of ALK Inhibition

Abstract

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.

Crizotinib-Induced Abnormal Signal Processing in the Retina

“…Therefore, the high frequency of visual disorder induced by crizotinib is unlikely to be attributable to ALK inhibition. This idea is consistent with previous findings indicating that an ALK-selective inhibitor did not produce significant changes on an electroretinogram [ 29 ]. Crizotinib also inhibits MET and ROS1 at nanomolar concentrations [ 25 ], while the inhibitory actions of alectinib on MET and ROS1 only occur at micromolar concentrations or higher [ 30 , 31 ].…”

“…We confirmed the expressions of ALK , MET , and ROS1 mRNA (receptor tyrosine kinases that serve as therapeutic targets in non-small-cell lung cancers [ 19 , 28 ]), in the mouse retina ( Fig 3 ). Immunoreactivity for ALK protein has been observed in mice [ 29 ]. Both crizotinib and alectinib inhibit ALK at nanomolar concentrations, but the incidence of visual disorder is higher for crizotinib.…”

“…Crizotinib also inhibits MET and ROS1 at nanomolar concentrations [ 25 ], while the inhibitory actions of alectinib on MET and ROS1 only occur at micromolar concentrations or higher [ 30 , 31 ]. However, the presence of MET [ 29 ] and ROS1 has not been confirmed at the protein level in the mouse retina. Therefore, it will be interesting to see if the actions of crizotinib on MET or ROS1 in the retina play a key role in the severe visual disorder.…”

Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement–positive non–small cell lung cancer treated with alectinib

“…Alectinib is a selective ALK inhibitor with little or no 17 days later, after alectinib discontinuation and institution of steroid therapy (d), showed diffuse ground glass opacities and infiltration in both lungs and their attenuation, respectively inhibitory activity for other protein kinases, whereas crizotinib inhibits multiple tyrosine kinases including ALK, ROS1, and MET. This difference may contribute to differences in the incidence of side effects such as visual disorders between crizotinib and alectinib [9]. On the other hand, the present case shows that ILD is induced by alectinib as well as by crizotinib, suggesting that ALK inhibition itself is a cause of ILD.…”

Meta-analysis of incidence and risk of severe adverse events and fatal adverse events with crizotinib monotherapy in patients with ALK-positive NSCLC

“…Notably, crizotinib is a multiple small-molecule inhibitor of ALK, MET and ROS1. Liu et al [ 34 ] suggested that the peripheral edema was more common in c-MET inhibition compared to crizotinib. As what mentioned before, this adverse event was observed significantly less in a Phase I study of ceritinib, as well as alectinib, which more specifically inhibits ALK without inhibition of c-MET [ 33 ].…”