Population Pharmacokinetic- Pharmacodynamic Analysis to Characterize the Effect of Empagliflozin on Renal Glucose Threshold in Patients With Type 1 Diabetes Mellitus

J Clin Pharmacol. 2018 May;58(5):640-649. doi: 10.1002/jcph.1051. Epub 2017 Dec 18.


Sodium glucose cotransporter 2 inhibitors increase urinary glucose excretion (UGE) by lowering the renal threshold for glucose (RTG ). We aimed to quantify the effect of the sodium glucose cotransporter inhibitor empagliflozin on renal glucose reabsorption in patients with type 1 diabetes mellitus (T1DM) using a mechanistic population pharmacokinetic-pharmacodynamic (PK-PD) model and to compare results with analyses in patients with type 2 diabetes mellitus (T2DM). The PK-PD model was developed using data from a randomized phase 2 study in which patients with T1DM received oral once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as an adjunct to insulin. The model assumed that UGE was dependent on plasma glucose and renal function and that empagliflozin lowered RTG . The final model was evaluated using visual predictive checks and found to be consistent with observed data. Calculated RTG with placebo was 181 mg/dL, and with empagliflozin (steady state) 1 mg and 2.5 mg was 53.4 mg/dL and 12.5 mg/dL, respectively. Empagliflozin 10 mg and 25 mg yielded negative RTG values, implying RTG was reduced to a negligible value. Although estimated PK-PD parameters were generally comparable between patients with T1DM and patients with T2DM, slight differences were evident, leading to lower RTG and higher UGE in patients with T1DM compared with patients with T2DM. In conclusion, the model provided a reasonable description of UGE in response to administration of empagliflozin and placebo in patients with T1DM.

Keywords: diabetes; modeling and simulation; pharmacodynamics; pharmacokinetics and drug metabolism; population pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Benzhydryl Compounds / administration & dosage*
  • Benzhydryl Compounds / pharmacokinetics
  • Benzhydryl Compounds / pharmacology
  • Clinical Trials, Phase II as Topic
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dose-Response Relationship, Drug
  • Female
  • Glucose / metabolism
  • Glucosides / administration & dosage*
  • Glucosides / pharmacokinetics
  • Glucosides / pharmacology
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Male
  • Middle Aged
  • Models, Biological*
  • Randomized Controlled Trials as Topic
  • Sodium-Glucose Transporter 2 Inhibitors / administration & dosage*
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacokinetics
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology


  • Benzhydryl Compounds
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • empagliflozin
  • Glucose