title: Tavaborole, a Novel Boron-Containing Small Molecule Pharmaceutical Agent for Topical Treatment of Onychomycosis: II. Prenatal and Postnatal Developmental Toxicity and Maternal Function Study.
abstract: 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.
authors.affiliation: Anacor Pharmaceuticals, Inc, Palo Alto, CA, USA vciaravino@anacor.com.
authors.forename: Vic
authors.initials: V
authors.lastname: Ciaravino
authors.affiliation: Anacor Pharmaceuticals, Inc, Palo Alto, CA, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Coronado
authors.affiliation: MPI Research, Mattawan, MI, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Lanphear
authors.affiliation: Charles River Laboratories, Horsham, PA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Hoberman
authors.affiliation: Anacor Pharmaceuticals, Inc, Palo Alto, CA, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chanda
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D001895:Boron / Q000627:therapeutic use / Q000633:toxicity*; D001896:Boron Compounds / Q000627:therapeutic use* / Q000633:toxicity*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use* / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D019055:No-Observed-Adverse-Effect Level; D014009:Onychomycosis / Q000188:drug therapy*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D018675:Toxicity Tests
chemical_list: D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C512998:tavaborole; D001895:Boron
keywords: developmental toxicity; rat reproductive study; reproductive development; tavaborole; teratology