2-Year animal carcinogenicity results for crisaborole, a novel phosphodiesterase 4 inhibitor for atopic dermatitis
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Vic Ciaravino1, Dina Coronado1, Cheryl Lanphear2
1Anacor Pharmaceuticals, Inc., 1020 E Meadow Circle, Palo Alto 94303, CA, USA.
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 300mg/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 (300mg/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 300mg/kg/day at exposures that were 3× the human area under the concentration-time curve (AUC24) and was nontumorigenic in female rats at 100mg/kg/day at exposures that were 1× the human AUC24.
Insights
Crisaborole, a topical PDE4 inhibitor for atopic dermatitis, showed no tumor risk in mice. Female rats developed benign reproductive tract tumors at high doses, but crisaborole was well-tolerated overall.
Area of Science:
- Pharmacology and Toxicology
- Dermatology
Background:
- Crisaborole is a novel topical nonsteroidal anti-inflammatory drug.
- It functions as a phosphodiesterase 4 (PDE4) inhibitor.
- It is indicated for mild to moderate atopic dermatitis.
Purpose of the Study:
- To evaluate the carcinogenic potential of crisaborole.
- This was assessed through 2-year nonclinical safety studies.
Main Methods:
- Mice received topical crisaborole ointment (2%, 5%, or 7%) daily for up to 104 weeks.
- Rats received oral crisaborole (30, 100, or 300 mg/kg/day) for up to 104 weeks.
- Systemic exposure, clinical signs, and tumor formation were monitored.
Main Results:
- Crisaborole was not tumorigenic in mice at any dose.
- No increased incidence of microscopic lesions was observed in mice.
- Female rats at 300 mg/kg/day showed increased benign granular cell tumors in the reproductive tract, without moribundity.
Conclusions:
- Crisaborole was well-tolerated and non-tumorigenic in mice.
- It was non-tumorigenic in male rats at exposures 3x human AUC24.
- It was non-tumorigenic in female rats at exposures 1x human AUC24.