title: Cutaneous lesions in the rat following administration of an irreversible inhibitor of erbB receptors, including the epidermal growth factor receptor.
abstract: CI-1033 (canertinib) is an irreversible inhibitor of the erbB family of transmembrane tyrosine kinase receptors, including the epidermal growth factor (EGF) receptor. Various inhibitors of the EGF receptor, including CI-1033, have resulted in cutaneous toxicity in humans as a common adverse event. In a chronic toxicity study in rats, CI-1033 produced cutaneous lesions with morphologic characteristics similar to that reported in man. Here the authors describe in detail the dermal changes observed, along with other noteworthy findings of that study. Male and female Wistar rats (15/sex/group) were administered CI-1033 for 27 weeks at 2.5, 5, or 10 mg/kg (15, 30, or 60 mg/m(2), respectively) by gavage. Control animals (15/sex) received vehicle alone (aqueous 0.5% methylcellulose) in a dose volume of 5 mL/kg. Six animals/sex/dose were included for toxicokinetic evaluations. Skin lesions were the primary drug-related toxicity and occurred at > or = 2.5 mg/kg in a dose-dependent fashion. The major gross lesions were papules that evolved into crusts and scales that were first observed in weeks 1 and 3, respectively. Alopecia developed in conjunction with the papular eruptions. Skin changes were most pronounced in females, possibly due to higher drug levels. In week 13, CI-1033 plasma AUC(0-24) values were 527 to 1980 ng.h/mL in males and 844 to 2920 ng x h/mL in females at 2.5 to 10 mg/kg. Microscopic changes could be described as 3 patterns that affected the tail and body (haired skin). Pattern 1 consisted of epidermal changes that started as a superficial, perivascular spongiotic dermatitis with evolving epidermal hyperplasia, scale-crusts, and areas of ulceration. Areas of hyperplasia on the tail were often associated with the development of new hair follicles. Pattern 2 was characterized by a suppurative to pyogranulomatous infundibular folliculitis. Pattern 3 consisted of abnormally oriented hair follicles with malformed hair shafts that were associated with a deeper (isthmic) folliculitis; this correlated with alopecia. Elevations in bone marrow myeloid counts correlated with a peripheral leukocytosis, consistent with inflammatory changes in the dermis. In addition, hepatic cholestasis and epithelial atrophy in the gastrointestinal tract and vagina occurred at > or = 2.5 mg/kg. In conclusion, CI-1033 produced cutaneous lesions involving the epidermis and hair follicle, and the morphologic characteristics were similar to that reported in clinical studies with various inhibitors of the EGF receptor. These changes are consistent with pharmacologic inhibition of the EGF receptor in these tissues and demonstrate that the rat can serve as an animal model for investigating the mechanisms for this toxicity.
authors.affiliation: Drug Safety Research & Development, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA. apbrown07@comcast.net
authors.forename: Alan P
authors.initials: AP
authors.lastname: Brown
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dunstan
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Courtney
authors.forename: Kay A
authors.initials: KA
authors.lastname: Criswell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Graziano
mesh_terms: D000284:Administration, Oral; D000505:Alopecia / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005499:Folliculitis / Q000139:chemically induced* / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D017444:Skin Diseases, Papulosquamous / Q000139:chemically induced* / Q000473:pathology; D018675:Toxicity Tests
chemical_list: D009025:Morpholines; C420268:Canertinib; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases