2-Year animal carcinogenicity results for crisaborole, a novel phosphodiesterase 4 inhibitor for atopic dermatitis. Issue 2 (August 2017)

• Record Type: Journal Article
• Authors: Ciaravino, Vic; Coronado, Dina; Lanphear, Cheryl; Chanda, Sanjay
• Is Part Of: Journal of dermatological science. Volume 87:Issue 2(2017:Aug.)
• Page Start: 116
• Page End: 122
• Publication Date: 2017-08
• Subjects: AD atopic dermatitis -- AUC24 area under the concentration-time curve from 0 to 24 h -- cAMP cyclic adenosine monophosphate -- CMC carboxymethylcellulose -- ECAC Executive Carcinogen Advisory Committee -- ICH International Conference on Harmonization -- IgE immunoglobulin E -- IL interleukin -- PDE4 phosphodiesterase 4 -- PGE2 prostaglandin E2 -- TCI topical calcineurin inhibitor -- TCS topical corticosteroid; Crisaborole -- Carcinogenicity -- Anti-inflammatory -- Phosphodiesterase inhibitor -- Atopic dermatitis; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2017.03.020
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: Crisaborole is a novel nonsteroidal topical PDE4 inhibitor being studied for AD. Two, 2-year nonclinical studies tested the carcinogenic potential of crisaborole. Dermal application above clinically relevant levels was nontumorigenic. Benign reproductive tract tumors in female rats were observed at ∼6× the human AUC. Crisaborole might be a safe nonsteroidal treatment for AD. Abstract: Background: Crisaborole is a novel, topical nonsteroidal, anti-inflammatory, phosphodiesterase 4 (PDE4) inhibitor for the treatment of mild to moderate atopic dermatitis. Objective: As part of a nonclinical safety testing program, these 2-year studies tested the carcinogenic potential of crisaborole. Methods: Crisaborole ointment, 2%, 5%, or 7%, was applied once daily topically to mice, and crisaborole was administered orally to rats at doses of 30, 100, or 300 mg/kg/day for up to 104 weeks. Systemic exposure to crisaborole and its metabolites, moribundity/death, clinical signs, and tumor formation were assessed in each study. Results: Crisaborole treatment was not tumorigenic in mice at any of the doses administered and did not increase the incidence of neoplastic or nonneoplastic microscopic lesions compared with controls. Oral administration of crisaborole at the high dose (300 mg/kg/day) to female rats increased the incidence of treatment-related benign granular cell tumors in the distal reproductive tract (uterus with cervix and vagina) but did not cause moribundity/death. Conclusion: Crisaborole was well tolerated and not tumorigenic in mice. It was not tumorigenic in male rats at 300 mg/kg/day at exposures that were 3× the human area under the concentration-time curve (AUC24 ) and was nontumorigenic in female rats at 100 mg/kg/day at exposures that were 1× the human AUC24 .