title: Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes.
abstract: OBJECTIVE
  To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure-response (E-R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1-100 mg once daily, duration ≤12 weeks) were used to develop E-R models for efficacy (glycosylated haemoglobin [HbA1c ], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E-R.
  
  
  RESULTS
  The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl(-1) ) and 10-25 mg every day empagliflozin targeted 80-90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation.
  
  
  CONCLUSIONS
  E-R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.
authors: Metrum Research Group LLC, Tariffville, CT.
authors: Matthew M
authors: MM
authors: Riggs
authors: Leo J
authors: LJ
authors: Seman
authors: Alexander
authors: A
authors: Staab
authors: Thomas R
authors: TR
authors: MacGregor
authors: William
authors: W
authors: Gillespie
authors: Marc R
authors: MR
authors: Gastonguay
authors: Hans J
authors: HJ
authors: Woerle
authors: Sreeraj
authors: S
authors: Macha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005960:Glucosides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000032:analysis; D006029:Glycosuria / Q000652:urine; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C517652:hemoglobin A1c protein, human; C570240:empagliflozin
keywords: BI 10773; SGLT2 inhibitor; empagliflozin; exposure−response analyses; type 2 diabetes