Mixed-effects modelling to quantify the effect of empagliflozin on renal glucose reabsorption in patients with type 2 diabetes.
OBJECTIVE
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.
Metrum Research Group, Tariffville, CT, USA.
J
J
Mondick
Metrum Research Group, Tariffville, CT, USA.
M
M
Riggs
Nippon Boehringer Ingelheim Co. Ltd, Hyogo, Japan.
T
T
Sasaki
Nippon Boehringer Ingelheim Co. Ltd, Hyogo, Japan.
A
A
Sarashina
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
U C
UC
Broedl
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
S
S
Retlich
D000368:Aged; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000493:pharmacokinetics*; D006029:Glycosuria / Q000188:drug therapy / Q000652:urine; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic; D065608:Renal Reabsorption / Q000187:drug effects*
D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C570240:empagliflozin; D005947:Glucose
SGLT2 inhibitor; empagliflozin; pharmacodynamics; pharmacokinetics; renal glucose reabsorption; type 2 diabetes