title: Evaluation of subchronic toxicity of GRD081, a dual PI3K/mTOR inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and beagle dogs.
abstract: GRD081, a newly developed dual PI3K/mTOR inhibitor, is now being considered for evaluation in phase I clinical trial. In this work, the subchronic toxicity of GRD081 in Sprague-Dawley (SD) rats and beagle dogs has been characterized. Rats and dogs received GRD081 orally (2, 5, 10 and 1, 2, 4 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days following a 14 days of recovery period. The treatment resulted in unscheduled mortality in rats receiving 5 mg/kg/day and 10 mg/kg/day. The adverse effects of GRD081 on rats and dogs mainly included myelosuppression, immunosuppression, hematological toxicity, and moderate liver, pancreas and kidney toxicity. These observations are consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of PI3K/mTOR signaling inhibitors. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of GRD081 was 1mg/kg/day for beagle dogs and less than 2 mg/kg/day for SD rats.
authors.affiliation: Center of Evaluation for Drug Safety, Second Military Medical University, Shanghai, China.
authors.forename: Zhenna
authors.initials: Z
authors.lastname: Xia
authors.forename: Tingting
authors.initials: T
authors.lastname: Gao
authors.forename: Ying
authors.initials: Y
authors.lastname: Zong
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Mao
authors.forename: Bojun
authors.initials: B
authors.lastname: Yuan
authors.forename: Guocai
authors.initials: G
authors.lastname: Lu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D059550:Toxicity Tests, Subchronic / Q000379:methods*
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: Dual PI3K/mTOR inhibitor; GRD081; Subchronic toxicity