Nonclinical Safety Evaluation of 2-Deoxy-D-Glucose Following Twice-Daily Oral Administration for 28 Days in Beagle Dogs.

Abstract

2-Deoxy-D-Glucose (2-DG) has anticonvulsant and antiseizure effects in rodent models and is in the development phase for novel antiseizure treatment. To evaluate potential toxicity, Beagle dogs (five/sex/group) were orally gavaged with either vehicle (deionized water) or 2-DG (5, 30, and 90 mg/kg BID) for 28 days followed by a 14-day recovery period. The safety endpoints evaluated were mortality, clinical observations, body temperature, respiratory assessment, body weights, food consumption, ophthalmic examinations, electrocardiograph (ECG), blood pressure, cardiac biomarker (NT-proBNP), and pathology. Toxicokinetic analysis was conducted after the first dose on days 1 and 28. The dose formulation analysis confirmed that 2-DG concentrations were within 93%-107% of the target concentrations. There were no 2-DG associated effects observed in mortality, clinical signs, body temperature, respiratory parameters, body weights, food consumption, ophthalmic examination, ECG, blood pressure, and NT-proBNP. There was an increase (∼1.7X) in aspartate transaminase on day 29, while histopathological evaluation revealed hepatic cytoplasmic alterations in 2 of 6 dogs on day 29 and only in 1 of 4 dogs on day 43 at 90 mg/kg BID. These changes were considered non-adverse because of minimal severity, reversibility trend after recovery period and no correlative increase in alanine transaminase. Toxicokinetic evaluation revealed dose dependent increases in C_max of ∼7.8, 39.5, and 114 μg/mL, and AUCs of 12.2, 70.8, and 202 h*μg/mL at 5, 30, and 90 mg/kg, respectively with T_max of ∼0.5-0.9 h and T_1/2 of ∼3.8-5.4 h. In conclusion, 90 mg/kg BID of 2-DG was considered as the No Observed Adverse Effect Level following 28-day administration in dogs.