2-Year animal carcinogenicity results for crisaborole, a novel phosphodiesterase 4 inhibitor for atopic dermatitis

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 (AUC 24 ) and was nontumorigenic in female rats at 100 mg/kg/day at exposures that were 1× the human AUC 24 .