RESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Compuestos de Boro/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Carcinogénesis/inducido químicamente , Neoplasias de los Genitales Femeninos/epidemiología , Inhibidores de Fosfodiesterasa 4/efectos adversos , Administración Cutánea , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Pruebas de Carcinogenicidad , Dermatitis Atópica/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Femenino , Neoplasias de los Genitales Femeninos/inducido químicamente , Humanos , Incidencia , Masculino , Ratones , Pomadas/efectos adversos , Inhibidores de Fosfodiesterasa 4/administración & dosificación , RatasRESUMEN
Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. The effects of tavaborole on gestation, parturition (delivery, labor), offspring development, and survival during the perinatal and postnatal periods were assessed in mated female rats. Females (F0 generation) were administered single daily oral (gavage) doses of 15, 60, or 100 mg/kg/d from gestation day 6 through lactation day 20. The females were allowed to deliver naturally and rear their offspring until lactation day 21, at which time the F0 females were euthanized. One male and female from each litter were selected (F1 generation) and retained for assessments, including growth, neurobehavior, fertility, and their ability to produce an F2 generation. Reproductive and offspring parameters were determined for the F1 and F2 generations, as applicable. F1 females and F2 pups were euthanized on postnatal day 7. In the F0 females, decreased activity was observed in the 100 mg/kg/d dose group. Excess salivation was observed in the 60 and 100 mg/kg/d dose groups (slight to moderate), however, this finding was not considered adverse. There were no tavaborole-related effects on the growth, viability, development, neurobehavioral assessments, or reproductive performance of the F1 generation. Survivability and mean body weight of the F2 pups were unaffected. The no observed adverse effect level (NOAEL) for maternal toxicity (F0 generation) was 60 mg/kg/d, based on the decreased activity observed in the 100 mg/kg/d dose group. The NOAEL for the offspring effects was ≥100 mg/kg/d, based on the lack of test article-related changes.
Asunto(s)
Compuestos de Boro/toxicidad , Compuestos de Boro/uso terapéutico , Boro/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Exposición Materna , Onicomicosis/tratamiento farmacológico , Administración Tópica , Animales , Animales Recién Nacidos , Peso Corporal , Boro/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Desarrollo Embrionario/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Masculino , Nivel sin Efectos Adversos Observados , Embarazo , Ratas , Ratas Sprague-Dawley , Reproducción/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. As part of the nonclinical development program, reproductive and developmental toxicity studies were conducted (rat oral fertility and early embryonic development, rat (oral) and rabbit (dermal) embryo-fetal development). There were no effects on fertility or reproductive performance at doses up to 300 mg/kg/d (107 times the maximum recommended human dose [MRHD] based on mean area under the plasma concentration-time curve comparisons). In the rat embryo-fetal development toxicity studies, teratogenicity was not observed at doses up to 100 mg/kg/d (29 times the MRHD). However, several treatment-related skeletal malformations and variations were observed at 300 mg/kg/d (570 times the MRHD). In rabbit embryo-fetal development toxicity studies dosed via oral or dermal administration, the no observable adverse effect level for maternal toxicity and embryo-fetal toxicity was 50 mg/kg/d (16 times the MRHD) and 5% (26 times the MRHD), respectively.
Asunto(s)
Compuestos de Boro/toxicidad , Compuestos de Boro/uso terapéutico , Boro/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Onicomicosis/tratamiento farmacológico , Reproducción/efectos de los fármacos , Administración Cutánea , Animales , Animales Recién Nacidos , Antifúngicos/uso terapéutico , Antifúngicos/toxicidad , Boro/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Masculino , Conejos , Ratas , Pruebas de ToxicidadRESUMEN
Tavaborole, a cyclized boronic acid, has been approved by the Food and Drug Administration for the topical treatment of toenail onychomycosis. This novel, low-molecular-weight pharmaceutical compound has broad-spectrum antifungal activity against dermatophytes, yeasts, and molds responsible for the disease. Tavaborole was tested in 2-year carcinogenicity studies in mice (once daily dermal administration) and rats (once daily by oral gavage) as part of the extensive nonclinical safety program. There was no evidence of tavaborole-related neoplasms observed in either study. Based on the data gathered from these 2 carcinogenicity studies, tavaborole is considered noncarcinogenic.