Mixed‐effects modelling to quantify the effect of empagliflozin on renal glucose reabsorption in patients with type 2 diabetes. Issue 3 (15th January 2016)

• Record Type: Journal Article
• Authors: Mondick, J.; Riggs, M.; Sasaki, T.; Sarashina, A.; Broedl, U. C.; Retlich, S.
• Is Part Of: Diabetes, obesity & metabolism. Volume 18:Issue 3(2016)
• Page Start: 241
• Page End: 248
• Publication Date: 2016-01-15
• Subjects: empagliflozin -- pharmacodynamics -- pharmacokinetics -- renal glucose reabsorption -- SGLT2 inhibitor -- type 2 diabetes; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.12597
• Languages: English
• ISSNs: 1462-8902

Abstract

Abstract : Aims: To quantify the effect of the sodium‐glucose co‐transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic–pharmacodynamic (PK–PD) model. Methods: Four phase I/II trials were used for model development. Empagliflozin's PK characteristics were characterized by a two‐compartmental model with sequential zero‐ and first‐order absorption. Urinary glucose excretion (UGE) was described as dependent on renal glucose filtration and reabsorption; splay of the glucose reabsorption/excretion curves was considered. The modelling assumed that empagliflozin lowers the maximum renal glucose reabsorption capacity and, thereby, the renal threshold for glucose (RTg). Covariate effects were investigated using a full covariate modelling approach, emphasizing parameter estimation. Results: The PK–PD model provided a reasonable description of the PK characteristics of empagliflozin and its effects on UGE across a range of renal function levels. Its parameters are consistent with reported values for renal physiology. Using this model, the effect of empagliflozin on renal glucose reabsorption was quantified. Steady‐state empagliflozin doses (1, 5, 10 and 25 mg) reduced RTg from 12.5 mmol/L [95% confidence interval (CI) 12.0, 13.1] to 5.66 (95% CI 4.62, 6.72), 3.01 (95% CI 2.33, 3.69), 2.53 (95% CI 1.83, 3.14) and 2.21 (95% CI 1.47, 2.84) mg/dl, respectively. Covariate analysis showed the effect of empagliflozin on UGE was not influenced, to a clinically relevant extent, by sex, age or race. Conclusions: A method for characterizing renal glucose reabsorption was developed that does not require complex glucose clamp experiments. These analyses indicate that empagliflozin provided concentration‐dependent RTg reductions, with 10 and 25 mg providing near‐maximum RTg‐lowering.