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

Abstract

BackgroundThe 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.MethodsThis 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.ResultsThis 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.ConclusionsCoadministration of metformin and RE was well tolerated in this study. The results support continued development of RE as a treatment for T2DM.Trial registrationClinicalTrials.gov, NCT00376038

Randomized trial showing efficacy and safety of twice‐daily remogliflozin etabonate for the treatment of type 2 diabetes

“…In contrast to the findings for twice‐daily dosing in the present study, no significant changes in LDL cholesterol were observed for once‐daily dosing with RE . The major difference between the present study and that by Sykes et al is the dosing regimen and overnight inhibition of SGLT2 by the twice‐daily dosing. An ongoing hypothesis is that overnight inhibition of SGLT2 occurs with either the twice‐daily RE or with the long half‐life SGLT2 inhibitors, such as dapagliflozin and canagliflozin.…”

Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes

“…Digital images were obtained by phosphorimaging. Abbreviations: bf-brown fat; ed-epdidymis; Hd-harderian gland; nm-nasal mucosa; pg-preputial gland; pr-prostate; sg-salivary gland; skn-non-pigmented skin; skp-pigmented skin; sv-seminal vesicles; ts-testis pharmacokinetic or dynamic interaction between these two anti-diabetic medicines [32]. Similarly, there are a number of expected coadministered drugs such as simvastatin, rosiglitazone and glimepiride that undergo extensive CYP-mediated metabolism [38][39][40].…”

“…Further the response was less than 20% of the response of rifampicin, an inducer of both CYP2B6 and 3A4. Overall, the CYP inhibition and induction data, along with the clinical observations to date [14,32], suggest that remogliflozin etabonate can be dosed with other drugs metabolized by CYP enzymes such as sulfonylureas, calcium channel blockers and statins without concern of a pharmacokinetic drug interaction.…”

Limited sampling strategy for determining metformin area under the plasma concentration–time curve

“…The LSS model was further validated using data from 16 previously published studies . The results (Table , Figure , Supplementary Figures S7 and S8) indicated that the AUC(0,24 h) predicted by the two point LSS model was in excellent agreement ( r 2 = 0.976, bias −1.0%, precision 4.3%) with the corresponding AUC(0,24 h) best estimates, over a wide range (3.8–22.4 μg h l −1 ) of AUC(0,24 h) values and under a variety of demographic, experimental and clinical conditions.…”