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

• Published in: Drug Design, Development and Therapy Vol. 16; pp. 2967 - 2980
• Main Authors: He, Xuemei, Gao, Xin, Xie, Panpan, Liu, Yuan, Bai, Wenjing, Liu, Yue, Shi, Aixin
• Format: Journal Article
• Language: English
• Published: Macclesfield Informa UK Limited 01.09.2022; Dove Medical Press Limited; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: Accumulation; Adult; Blood Glucose; Blood pressure; Body mass index; China; chinese healthy subjects; Chronic illnesses; Complications; Complications and side effects; Creatinine; Dextrose; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1; Diabetes therapy; Diabetics; Drug Design, Development and Therapy; Electrocardiography; Enzymes; Glucose; Glycosides; Healthy Volunteers; Heart failure; Humans; Hypoglycemia; Insulin; Kidney diseases; Laboratories; lx4211; Metabolism; Metabolites; Mortality; Na+/glucose cotransporter; Original Research; Parameters; Pharmacodynamics; Pharmacokinetics; Pharmacology; Placebos; Plasma; Population; RM1-950; Safety; sotaglifozin; Therapeutics. Pharmacology; Type 2 diabetes; China; Beijing China; United States > US
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/dddt.s372575

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 sotaglifozin. Methods: This was a Phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. Healthy subjects received 200mg or 400mg of sotaglifozin or placebo once daily for 8 days, respectively. PK parameters of sotaglifozin 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 sotaglifozin 200 mg (N = 9), sotaglifozin 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.sub.max] and AUCtau were 1.89-fold and 1.70-fold. The pooled accumulation ratio of sotaglifozin was 1.57 for [C.sub.max] and 1.84 for AUCtau. LX4211-GLU had similar PK features. UGE was significantly elevated in both sotaglifozin 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 sotaglifozin per day were well tolerated in Chinese healthy subjects. Keywords: diabetes mellitus, sotaglifozin/LX4211, sodium-glucose cotransporter, pharmacokinetics, pharmacodynamics, safety