Abstract
Purpose
Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2
inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM).
This study aimed to investigate the effects of meal intake on the pharmacokinetic
properties of henagliflozin, and to understand the excretion pathways of henagliflozin
in humans.
Methods
In this Phase I, randomized, open-label, single-dose, two-period crossover study,
12 healthy male Chinese volunteers were randomized to receive either henagliflozin
10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition,
or the reverse schedule, with the two administrations separated by a washout period
of at least 7 days. Samples of blood, urine, and feces were collected and analyzed
for the investigation of the pharmacokinetic profile and excretion pathways in the
fasted and fed conditions. Any adverse events that occurred throughout the study were
recorded for tolerability assessment.
Findings
After the administration of a single oral dose of henagliflozin, mean (SD) plasma
AUC0–∞ and Cmax were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state
and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The
fed/fasted ratios (90% CIs) of the geometric mean values of Cmax, AUC0–t, and AUC0–∞ were 64% (54%–76%), 80% (76%–85%), and 80% (76%–85%), respectively. The median (range)
Tmax was prolonged from 1.5 (1–3) hours in the fasted condition to 2 (1.5–6) hours in
the fed condition. Mass-balance testing revealed that henagliflozin was eliminated
primarily as the parent drug in feces and as glucuronide metabolites in urine. In
the fasted state, the cumulative excretion percentages of the parent drug and its
metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values
in the fed condition were changed to 50.4% and 25.5%, respectively. These findings
suggest that postprandial administration decreases the absorption rate and the extent
of henagliflozin exposure in humans, but has no effect on the metabolism or elimination
of the drug.
Implications
In the present study, the consumption of a high-fat meal prior to henagliflozin administration
was associated with reductions in AUC0–∞ and Cmax of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic
findings on henagliflozin, this slight change may not have clinical significance.
Mass balance of henagliflozin in humans was achieved with ∼75% of the administered
dose recovered in excretions within 4 days after administration whether in the fasted
or fed state. These findings suggest that henagliflozin tablets can be administered
with or without food.
Key words
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Article info
Publication history
Published online: August 06, 2021
Accepted:
July 5,
2021
Identification
Copyright
© 2021 Elsevier Inc.
