Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus

Abstract

Background: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the renal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widely used for the treatment of T2DM.

Methods: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin alone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable duration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for the duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma glucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid) assessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling occurred on Day 3 of each treatment period.

Results: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin did not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly lower for remogliflozin and its metabolite after co-administration with metformin compared with administration of RE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in lactic acid.

Conclusions: Coadministration of metformin and RE was well tolerated in this study. The results support continued development of RE as a treatment for T2DM.

Trial registration: ClinicalTrials.gov, NCT00376038.

Figures

Figure 1

Mean metformin concentration (and standard deviation) vs. time profiles with and without remogliflozin etabonate, n = 13.

Figure 2

Median remogliflozin etabonate (prodrug) concentration vs. time profiles with and without metformin, n = 13. (Median data is presented in this plot because the majority of the samples were below the lower limit of quantification).

Figure 3

Mean remogliflozin (active entity) concentration (and standard deviation) vs. time profiles with and without metformin, n = 13.

Figure 4

Mean GSK279782 (active metabolite) concentration (and standard deviation) vs. time profiles with and without metformin, n = 13.

Figure 5

Fasting plasma glucose concentration (FPG; mmol/L) – Change from baseline (pre- dose on Day 1 of each treatment period). MET BID, metformin 500 mg every 12 hours; RE BID, remogliflozin etabonate 500 mg every 12 hours; MET + RE BID, metformin 500 mg + remogliflozin etabonate 500 mg every 12 hours. Mean (and standard deviation) baseline FPG values for each treatment period: MET BID: 6.72 (1.88); RE BID, 6.98 (2.06); MET + RE BID, 6.42 (1.15).

Figure 6

Lactic acid concentration by treatment (normal range of 0.5 to 2.2 mmol/L). MET BID, metformin 500 mg every 12 hours; RE BID, remogliflozin etabonate 500 mg every 12 hours; MET + RE BID, metformin 500 mg + remogliflozin etabonate 500 mg every 12 hours.