Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration.

Background: Henagliflozin, a novel selective inhibitor of sodium-glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus.

Purpose: To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers.

Methods: Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5-200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25-100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies.

Findings: No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a T of 1.5-3 h, and then eliminated from plasma with a half-life of 11-15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5-200 mg (SAD) and 1.25-100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%-5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration.

Implications: Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.