Abstract
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.