title: 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.
abstract: 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 [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01571661.
authors.forename: Anita
authors.initials: A
authors.lastname: Kapur
authors.forename: Robin
authors.initials: R
authors.lastname: O'Connor-Semmes
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Hussey
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dobbins
authors.forename: Wenli
authors.initials: W
authors.lastname: Tao
authors.forename: Marcus
authors.initials: M
authors.lastname: Hompesch
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Smith
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Charles D
authors.initials: CD
authors.lastname: James
authors.forename: Imao
authors.initials: I
authors.lastname: Mikoshiba
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Nunez
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004573:Electrolytes / Q000652:urine; D005260:Female; D005960:Glucosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D004573:Electrolytes; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D011720:Pyrazoles; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C532127:remogliflozin etabonate