Exposure−response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes. (December 2014)

• Record Type: Journal Article
• Authors: Riggs, Matthew M.; Seman, Leo J.; Staab, Alexander; MacGregor, Thomas R.; Gillespie, William; Gastonguay, Marc R.; Woerle, Hans J.; Macha, Sreeraj
• Is Part Of: British journal of clinical pharmacology. Volume 78:Number 6(2014:Dec.)
• Page Start: 1407
• Page End: 1418
• Publication Date: 2014-12
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12453
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12453-sec-0001" sec-type="section"> <title>Aims</title> <p>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).</p> </sec> <sec id="bcp12453-sec-0002" sec-type="section"> <title>Methods</title> <p>Five randomized, placebo‐controlled, multiple oral dose studies of empagliflozin in patients with T2DM (<italic>n</italic> = 974; 1–100 mg once daily, duration ≤12 weeks) were used to develop E−R models for efficacy (glycosylated haemoglobin [HbA<sub>1c</sub>], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (<italic>n</italic> = 748, 12 weeks) were used to evaluate tolerability E−R.</p> </sec> <sec id="bcp12453-sec-0003" sec-type="section"> <title>Results</title> <p>The efficacy model predicted maximal decreases in FPG and HbA<sub>1c</sub> of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 m<sc>m</sc> (144 mg dl<sup>−1</sup>) and 10–25 mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (<italic>n</italic> = 4), urinary tract infection (<italic>n</italic> = 17) or genital/vulvovaginal‐related (<italic>n</italic> = 16) events, although low prevalence rates may have precluded more accurate evaluation.</p> </sec> <sec id="bcp12453-sec-0004" sec-type="section"> <title>Conclusions</title> <p>E−R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.</p> </sec> </abstract>