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

Henagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. Two clinical studies w...

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Published in:Clinical therapeutics 2021-02, Vol.43 (2), p.396-409
Main Authors: Zhang, Yi-fan, Liu, Yan-mei, Yu, Chen, Wang, Ya-ting, Zhan, Yan, Liu, Hai-yan, Zou, Jian-jun, Jia, Jing-ying, Chen, Qian, Zhong, Da-fang
Format: Article
Language:English
Subjects:
Adverse events
Blood pressure
Clinical trials
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Dosage
Drug dosages
Electrolytes
Excretion
Glucose
henagliflozin
Hospitals
Inhibitors
Laboratories
Metabolites
Na+/glucose cotransporter
Oral administration
Particle size
Pharmacodynamics
Pharmacokinetics
Pharmacology
Plasma
SGLT-2 inhibitors
Sodium
Urine
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Summary:Henagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. 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. 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 Tmax 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. 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. •Henagliflozin was well tolerated in healthy subjects.•Henagliflozin was rapidly absorbed and exhibited dose-proportional PK profiles.•The UGE24h was dose-dependently increased to henagliflozin and saturated at > 25 mg.•Henagliflozin did not change blood glucose in healthy subjects.•Henagliflozin did not affect urinary electrolytes excretion in healthy subjects.
ISSN:0149-2918
1879-114X
DOI:10.1016/j.clinthera.2020.12.012