Mathematical Modeling of Renal Sodium, Potassium, and Glucose Dynamics in Diabetic and Non-Diabetic Simulated Populations

Authors: Battista C, Cheng L, Hamzavi N, Bhargava P, Siler SQ
Conference: ACoP
Keywords: absorption, diuretic, glucose, potassium, quantitative systems pharmacology (QSP), quantitative systems pharmacology (QSP) model, Type 2 diabetes
Division: DILIsym Services

Objective

Type 2 diabetic (T2D) patients often exhibit reduced systolic and diastolic functions, which can place them at an increased risk of heart failure1, but diuretic therapies can mitigate the risk of heart failure in these patients. To enable future efficacy predictions of diuretics, a quantitative systems pharmacology (QSP) model was developed that includes dynamic transport of solutes across different nephron segments, enabling the ability to accurately capture renal sodium, potassium, and glucose reabsorption dynamics and urinary excretion in response to novel treatments.

Methods

The sodium water regulation model developed by Niederalt et. al² was expanded in this work to represent handling of potassium and glucose. This work altered the model to dynamically represent active transport of solutes via explicit inclusion of primary transporters/channels involved in glucose, sodium, and potassium reabsorption (SGLT1, SGLT2, ROMK, NKCC2, Na/K-ATPase, and ENaC) along the nephron. The model was calibrated to a baseline, healthy human using publicly available data for solute reabsorption³-⁶ and solute urinary excretion⁷,⁸. Simulated populations with inter-individual variability in renal physiology and sodium, potassium, and glucose pathways were developed to capture inter-patient variability reported in the literature for nondiabetic and T2D populations⁷, ⁹-¹⁷. The model can be used explore potential distributions of key outputs in the simulated populations. Exploratory simulations were conducted to qualitatively assess the impact of transporter inhibition on urinary sodium and potassium excretion and results were qualitatively compared with known effects of on-market diuretics.

Conclusion

  • The expanded QSP model accurately captures reabsorption and excretion data for glucose, sodium, and potassium in simulated cohorts of nondiabetic or type 2 diabetes patients.
  • Exploratory simulations of transporter inhibition suggest that the model properly captures transporter effects and qualitatively reproduces known clinical responses in potassium and sodium urine output.
  •  The QSP model of renal potassium and sodium handling provides the ability to simulate responses to diuretic treatments with the aim of predicting reductions in the risk of heart failure.

Christina Battista, Limei Cheng, Nader Hamzavi, Pallavi Bhargava, Scott Q Siler

Presented at the American Conference on Pharmacometrics Annual Meeting (ACoP13) October 30 – November 2, 2022, Aurora, Colorado