Exposure−response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes

• Published in: British journal of clinical pharmacology 2014-12, Vol.78 (6), p.1407-1418
• Main Authors: Riggs, Matthew M., Seman, Leo J., Staab, Alexander, MacGregor, Thomas R., Gillespie, William, Gastonguay, Marc R., Woerle, Hans J., Macha, Sreeraj
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Benzhydryl Compounds - pharmacokinetics; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; BI 10773; Blood Glucose - analysis; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dose-Response Relationship, Drug; empagliflozin; exposure−response analyses; Female; Glucosides - pharmacokinetics; Glucosides - pharmacology; Glucosides - therapeutic use; Glycated Hemoglobin A - analysis; Glycosuria - urine; Humans; Hypoglycemic Agents - therapeutic use; Male; Middle Aged; Models, Biological; Pharmacokinetic Dynamic Relationships; Randomized Controlled Trials as Topic; SGLT2 inhibitor; Sodium-Glucose Transporter 2 - antagonists & inhibitors; type 2 diabetes
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12453

Aims 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.