First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus

BMC Clinical Pharmacology

Derek J Nunez³  Imao Mikoshiba¹  Charles D James Jr⁴  Joseph W Polli³  Glenn A Smith³  Marcus Hompesch²  Wenli Tao³  Robert L Dobbins³  Elizabeth K Hussey³  Robin O’Connor-Semmes³  Anita Kapur³ 

[1] Kissei Pharmaceutical Company LTD, Matsumoto City, Japan;Profil Institute for Clinical Research, Chula Vista, CA, USA;GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA;Tandem Labs, Durham, NC, USA

关键词: Type 2 diabetes mellitus;    Pharmacodynamics;    Pharmacokinetics;    Sodium-dependent glucose transporter 2 inhibitor;    Remogliflozin etabonate;   

Others  :  860596
DOI  :  10.1186/2050-6511-14-26

 received in 2012-02-17, accepted in 2013-04-12,  发布年份 2013

【 摘 要 】

Background

Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans.

Methods

This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661.

Results

RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [C_max;T_max] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T_½ of ~25 min; mean plasma T_½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes.

Conclusions

The results support progression of RE as a potential treatment for T2DM.

Trial registration

ClinicalTrials.govNCT01571661

【 授权许可】

   
2013 Kapur et al.; licensee BioMed Central Ltd.

【 图 表 】

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