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

BMC Clinical Pharmacology

Robert L Dobbins¹  Charles D James²  Joseph W Polli¹  Bryan Rafferty¹  Wenli Tao¹  Robin O’Connor-Semmes¹  Anita Kapur¹  Elizabeth K Hussey¹ 

[1]GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA

[2]Tandem Labs, Durham, NC, USA

关键词: Type 2 diabetes mellitus;    Pharmacokinetics;    Metformin;    SGLT2 inhibitor;    Remogliflozin etabonate;   

Others  :  860606
DOI  :  10.1186/2050-6511-14-25

 received in 2012-02-17, accepted in 2013-04-18,  发布年份 2013

【 摘 要 】

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 C_max 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

【 授权许可】

   
2013 Hussey et al.; licensee BioMed Central Ltd.

【 图 表 】

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