Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Sotagliflozin After Multiple Ascending Doses in Chinese Healthy Subjects

Xuemei He; Xin Gao; Panpan Xie; Yuan Liu; Wenjing Bai; Yue Liu; Aixin Shi

doi:10.2147/DDDT.S372575

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Sotagliflozin After Multiple Ascending Doses in Chinese Healthy Subjects

Drug Des Devel Ther. 2022 Sep 6:16:2967-2980. doi: 10.2147/DDDT.S372575. eCollection 2022.

Authors

Xuemei He¹, Xin Gao¹, Panpan Xie¹, Yuan Liu¹, Wenjing Bai¹, Yue Liu¹, Aixin Shi¹

Affiliation

¹ Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

Abstract

Background: Sotagliflozin (LX4211) is a dual inhibitor of sodium-glucose cotransporter (SGLT)1 and SGLT2 being investigated to improve glycemic control in adults with diabetes. This study was firstly conducted to assess the pharmacokinetic (PK), pharmacodynamic (PD) profiles, safety and tolerability in Chinese healthy subjects after administration of sotagliflozin.

Methods: This was a Phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. Healthy subjects received 200mg or 400mg of sotagliflozin or placebo once daily for 8 days, respectively. PK parameters of sotagliflozin and LX4211-GLU (main metabolite), as measured by blood samples collected pre/postdose on Day 1/predose on Day 2-Day 8/postdose on Day 8, and PD parameters of absolute urinary glucose excretion (UGE) were determined. Treatment-emergent adverse events (TEAEs) were evaluated.

Results: Overall, 24 subjects were enrolled and randomized to sotagliflozin 200 mg (N = 9), sotagliflozin 400 mg (N = 9), or placebo (N = 6) group, and all subjects completed the study. Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree (less than 2-fold) of accumulation. Sotagliflozin plasma concentrations peaked at 1.0 h post dose. On Day 8, the estimated increases for C_max and AUC_tau were 1.89-fold and 1.70-fold. The pooled accumulation ratio of sotagliflozin was 1.57 for C_max and 1.84 for AUC_tau. LX4211-GLU had similar PK features. UGE was significantly elevated in both sotagliflozin groups relative to the placebo group. All TEAEs were mild and resolved without sequelae. There were no serious AEs or other significant TEAEs.

Conclusion: Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree of accumulation. Both 200 mg and 400 mg sotagliflozin per day were well tolerated in Chinese healthy subjects.

Keywords: diabetes mellitus; pharmacodynamics; pharmacokinetics; safety; sodium-glucose cotransporter; sotagliflozin/LX4211.

Publication types

Clinical Trial, Phase I
Randomized Controlled Trial

MeSH terms

Adult
Blood Glucose / metabolism
China
Diabetes Mellitus, Type 1* / drug therapy
Glycosides
Healthy Volunteers
Humans

Substances

Blood Glucose
Glycosides
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

Grants and funding

This study was initiated and funded by Sanofi. Sanofi ended collaboration with Lexicon Pharmaceuticals, Inc. for Sotagliflozin. At the time of study conducted, there was no regulatory pathway to transfer sponsorship during the conduct of ongoing studies. Sanofi provided sotagliflozin/placebo and was responsible for the collection of the data and statistical analysis of the study data. Lexicon Pharmaceuticals, Inc. was responsible for writing the Clinical Study Report.