J. Mondick (1), M. M. Riggs (1), S. Macha (2), A. Staab (3), G. Kim (4), H. J. Woerle (4), U. C. Broedl (4), S. Retlich (3)
(1) Metrum Research Group LLC, Tariffville, CT, USA; (2) Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; (3) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; (4) Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Objectives: Empagliflozin, a selective and potent SGLT2 inhibitor, reduces renal glucose reabsorption by lowering the renal threshold for glucose (RTG) leading to increased urinary glucose excretion (UGE) and decreased plasma glucose (PG) in patients with type 2 diabetes mellitus (T2DM). This analysis aimed to quantify the impact of empagliflozin on RTG by characterizing the relationship between empagliflozin exposure and UGE in patients with T2DM using nonlinear mixed-effects modeling.
Methods: A pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using UGE, PG, PK and estimated glomerular filtration rate (eGFR) data from three Phase I/II trials (N=223; placebo, empagliflozin 1 to 100 mg once daily [QD]). The model assumed that when PG>RTG, UGE increased with increasing PG and eGFR; and when PG≤RTG slight glucose leakage into urine occurred (estimated as fraction reabsorbed [FRAC]). Reabsorption was estimated by a nonlinear function parameterized in terms of maximum reabsorbed glucose concentration (Gmax) and PG concentration to reach half maximum transport (Km). Maximum inhibitory effect (Imax) and half maximal inhibitory concentration (IC50) described inhibition of renal glucose absorption. RTG was calculated as the difference between maximum reabsorption (including drug effect) and KM. The model was evaluated via bootstrap and external predictive check of an empagliflozin renal impairment study.