title: 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.
authors.affiliation: *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 chang-ning.liu@pfizer.com.
authors.forename: Chang-Ning
authors.initials: CN
authors.lastname: Liu
authors.affiliation: *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.
authors.forename: Nagappan
authors.initials: N
authors.lastname: Mathialagan
authors.affiliation: *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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lappin
authors.affiliation: *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.
authors.forename: Jay
authors.initials: J
authors.lastname: Fortner
authors.affiliation: *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.
authors.forename: Chris
authors.initials: C
authors.lastname: Somps
authors.affiliation: *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.
authors.forename: Gary
authors.initials: G
authors.lastname: Seitis
authors.affiliation: *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.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Johnson
authors.affiliation: *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.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.affiliation: *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.
authors.forename: Diane
authors.initials: D
authors.lastname: Matsumoto
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000077547:Crizotinib; D003623:Dark Adaptation / Q000187:drug effects*; D004285:Dogs; D004596:Electroretinography; D005071:Evoked Potentials; D006801:Humans; D007150:Immunohistochemistry; D008027:Light; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010775:Photic Stimulation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases
keywords: PF–02341066; PF–06463922; anaplastic lymphoma kinase; electroretinogram; retina, Xalkori®