Abstract 4385: Effect on retinal function as a mechanism for vision disorders with crizotinib (PF-02341066)

Abstract

Crizotinib is a small-molecule receptor tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) and c-Met. Crizotinib has been shown to be effective in patients with ALK-positive non-small cell lung cancer. One common adverse event that has been observed is a grade 1 vision disorder (∼45% of patients) characterized as seeing shadows or streaks during changes in lighting conditions. Onset occurs during the first weeks of treatment, with most cases improving with continued treatment and not requiring treatment discontinuation. Such vision disorders were not predicted from preclinical toxicological evaluation of crizotinib. To further understand the possible mechanism of this vision disorder, a rat electroretinography (ERG) study was conducted to determine if retinal function is altered following repeat-dose administration of crizotinib. Male Long-Evans rats (8/group) were administered crizotinib by oral gavage at a dose of 100 mg/kg/day for up to 29 days, during which an evaluation of in-life parameters (clinical signs, body weight, and food consumption), ophthalmic examinations, and ERG were performed. As part of the ERG assessment, five light-stimulation protocols were applied to test scotopic (dark-adapted) and photopic (light-adapted) luminance responses, photopic and scotopic adaptometry, and photopic flicker responses. Terminal plasma and vitreous fluid were examined for crizotinib concentrations in main study animals, and a toxicokinetic profile was obtained from a satellite group of 6 animals. Results of the ERG measurements identified a statistically significant (∼30%) reduction in mean b-wave amplitude relative to control during the initial 16 and 32 minutes of dark adaptation on Days 15 (p<0.05) and 29 (p<0.01), respectively. The magnitude of the reduction did not worsen between Days 15 and 29. Following 2 hours of dark adaptation, b-wave amplitudes were comparable between control and crizotinib-treated animals on both Days 15 and 29. There were no crizotinib-related effects observed for any other ERG parameters or during ophthalmologic examinations. Plasma exposures were ∼6-fold those associated with vision disorders in patients, and vitreous humor concentrations were 0.66-fold those in plasma at an equivalent time post-dose. Results from this preclinical model show that crizotinib causes significant reductions in the rate of retinal dark adaptation, but not the ability to achieve full dark adaptation. Vision disorders reported in the clinical setting may thus be due to direct effects on the retina rather than a central CNS effect. Whether this is a pharmacologically mediated effect at ALK or c-Met receptors expressed in retina or an off-target effect is not clear. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4385. doi:10.1158/1538-7445.AM2011-4385

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

“…Thus, changes in retinal dark adaptation in the rat were observed at drug levels only slightly above those associated with visual disturbance in the clinic. Visual system AEs in patients were often reported during light level transitions, although typically from dark to light rather than light to dark (Matsumoto et al, 2011). Additionally, evaluations of ALK and c-Met expression in the retina show similar expression patterns across rat and human.…”

Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: An expert consensus

“…Electroretinography studies in rats have provided evidence of a direct effect of crizotinib on retinal function, specifically a decreased rate of dark adaptation [22]. Since visual disturbances are generally transient, are not found to be bothersome, and do not affect patients' quality of life, they do not require specific intervention.…”