title: Early Vaginal Opening in Juvenile Female Rats Given BRAF-Inhibitor Dabrafenib Is Not Associated with Early Physiologic Sexual Maturation.
abstract: Dabrafenib (DAB), an inhibitor of BRAF kinase activity, is approved for metastatic melanoma with a BRAF V600E mutation. In support of pediatric cancer development, a nonclinical juvenile rat toxicity study was conducted in which females had early vaginal opening (VO). It was hypothesized that the early VO was not indicative of sexual maturation, but a result of a local effect on the vagina. An investigative study was conducted that mimicked the definitive study design, with rats given DAB or vehicle orally from Postnatal Day (PND) 7 to 35 and with necropsy subsets just before VO, at the first and second estrus, along with age-matched controls. Histopathology was performed on reproductive tissues, including immunohistochemistry for BRAF expression. VO occurred earlier in DAB females than in controls (PND 27.2 vs. 31.5); however, the timing of the first estrus was unaffected (PND 34.0 vs. 33.0). DAB-treated females evaluated just before VO (PND 22.0) had mostly immature reproductive tracts with no evidence of ovulation, similar to age-matched controls; however, DAB-treated females had keratinized and histologically open vaginas. Also, there was raised skin around the urogenital area, which correlated with hyperplasia/keratosis of the vulvar skin and keratinization of the distal vagina. BRAF expression (evaluated in controls) was localized to these tissues. Thus, early VO in rats given DAB likely represents a local effect accelerating vaginal keratinization to become open and not accelerated sexual maturation.
authors.affiliation: Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Posobiec
authors.affiliation: Vet Path Services, Inc, Mason, Ohio.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Vidal
authors.affiliation: Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Angela
authors.initials: A
authors.lastname: Hughes-Earle
authors.affiliation: Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Laffan
authors.affiliation: Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hart
mesh_terms: D000818:Animals; D004971:Estrus / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D010091:Oximes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation / Q000187:drug effects*; D014621:Vagina / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: postnatal evaluation; risk assessment; safety assessment; vagina