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- W2593669937 abstract "Objective: To determine the toxicological, behavioral, and neurohistopathological effects of deflazacort in juvenile rats from Postnatal Day (PND) 21 to 80 with recovery at PND 138.Background: Marathon is developing deflazacort for the treatment of boys with Duchenne Muscular Dystrophy (DMD). Despite extensive clinical experience with deflazacort, its effects on growth and development have not been characterized in juvenile animals.Methods: Juvenile rats (N=20/sex/group) were administered 0, 0.1, 0.3, or 1.0 mg/kg/day deflazacort from PND21-80 and assessed for clinical observations, body weight, food consumption, ophthalmologic examinations, behavioral assessments (FOB, acoustic startle response, motor activity, Morris Water Maze), clinical pathology (hematology, clinical chemistry, urinalysis), bone measurements, macroscopic and microscopic observations, male reproductive assessments, organ weights, and neurohistopathology evaluations. A satellite group of juvenile rats was dosed to provide toxicokinetic exposures.Results: At the end of the dosing period, deflazacort-related effects were dose-dependent and included: decreases in mean body weight gain and food consumption; increases in stereotypical behavior and motor activity at higher doses; mild to marked deceases in total white blood cell and lymphocyte counts, mild increases in neutrophil counts, and mild to moderate decreases in cholesterol; decreases in femur lengths; decreases in adrenal glands, spleen, and thymus weights; and correlative histopathological findings of decreased cellularity in the target lymphoid tissues. There were no deflazacort-related findings on ophthalmic exams, spermatogenesis, or neurohistopathology. At the end of the recovery period, deflazacort-related effects demonstrated complete recovery (clinical pathology, histopathology) or near complete recovery (body weight gain, neurobehavioral assessments).Conclusions: Deflazacort-related effects on growth and development in juvenile rats were consistent with the primary pharmacology of the drug. All findings demonstrated signs of recovery upon cessation of dosing. Exposures to the active metabolite of deflazacort in the rats were about 2-fold higher than exposures anticipated in boys with DMD at therapeutic doses of deflazacort. Disclosure: Dr. Wanaski has received personal compensation for activities with Marathon Pharmaceuticals, LLC. Dr. Lewis has nothing to disclose. Dr. Dubow has received personal compensation for activities with Marathon Pharmaceuticals, LLC. Dr. Meyer has received personal compensation for activities with Marathon Pharmaceuticals. Dr. Cunniff has received personal compensation for activities with Marathon Pharmaceuticals, LLC." @default.
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- W2593669937 date "2016-04-05" @default.
- W2593669937 modified "2023-09-27" @default.
- W2593669937 title "Effects of Deflazacort on Growth and Development in Juvenile Rats (P5.097)" @default.
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