Pharmacokinetics, Pharmacodynamics, And Tolerability Of Single- And Multiple-Dose Of Janagliflozin, A Sodium-Glucose Cotransporter 2 (Sglt2) Inhibitor, In Healthy Chinese Subjects

Objectives: Janagliflozin (JGZ) is a novel SGLT2 inhibitor for the treatment of type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption and increasing urinary glucose excretion. The purposes of the studies were 1) to investigate the PK, PD, and tolerability of JGZ in healthy Chinese subjects, 2) to provide a guidance for the selection of dosing regimens in further clinical studies. Methods: Two randomized, double-blind, placebo-controlled studies were sequentially conducted, including one single-ascending dose (SAD) study and one multiple-ascending dose (MAD) study. In the SAD study, 56 subjects were randomized to receive 10, 25, 50, 100, 200, 300, or 450 mg JGZ or placebo. In the MAD study, 42 subjects were randomized to receive 50, 100, 200 mg JGZ or placebo as loading dose on Day 1, and then 25, 50, 100 mg JGZ or placebo once-daily from Day 2 to Day 14. The blood and urine samples were collected at prespecified time points, and the PK parameters, PD response exhibited in 24 h urinary glucose excretion (UGE), and tolerability were assessed. Results: JGZ was readily absorbed with Tmax being 2.0∼4.5 h. The mean steady-state T1/2 was about 26∼30 h. The plasma exposure of JGZ increased in a roughly dose-dependent manner. The mean 24 h UGE ranged from about 18∼85 g in SAD study, with a dose-dependent increasing trend. The mean 24 h UGE were approximately 40, 43, and 50 g at steady state with 25, 50, and 100 mg JGZ, respectively, indicating no significant increase over the dose range of 25 to 100 mg. The adverse events in both studies were mostly mild with no serious adverse event or adverse event leading to discontinuation. Conclusions: In healthy Chinese subjects, JGZ was generally well tolerated and had favorable PK and PD profiles supporting a once-daily dosing regimen. The present studies suggest JGZ 25 and 50 mg could be the clinically recommended doses, which need to be further investigated in T2DM patients. Disclosure H. Liu: Research Support; Self; XuanZhu Pharma Co., Ltd., Jinan, Shandong, China. L. Song: Research Support; Self; XuanZhu Pharma Co., Ltd., Jinan, Shandong, China. X. Xiao: None. J. Jiang: Research Support; Self; XuanZhu Pharma Co., Ltd., Jinan, Shandong, China. P. Hu: Research Support; Self; XuanZhu Pharma Co., Ltd., Jinan, Shandong, China. D. Liu: Research Support; Self; XuanZhu Pharma Co., Ltd., Jinan, Shandong, China. Funding XuanZhu Pharma Co., Ltd.