A Quantitative Systems Pharmacology Kidney Model of Diabetes Associated Renal Hyperfiltration and the Effects of SGLT Inhibitors

Abstract

The early stage of diabetes mellitus is characterized by increased glomerular filtration rate (GFR), known as hyperfiltration, which is believed to be one of the main causes leading to renal injury in diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to be able to reverse hyperfiltration in some patients. We developed a mechanistic computational model of the kidney that explains the interplay of hyperglycemia and hyperfiltration and integrates the pharmacokinetics/ pharmacodynamics (PK/PD) of the SGLT2i dapagliflozin. Based on simulation results, we propose kidney growth as the necessary process for hyperfiltration progression. Further, the model indicates that renal SGLT1i could significantly improve hyperfiltration when added to SGTL2i. Integrated into a physiologically based PK/PD (PBPK/PD) Diabetes Platform, the model presents a powerful tool for aiding drug development, prediction of hyperfiltration risk, and allows the assessment of the outcomes of individualized treatments with SGLT1-inhibitors and SGLT2-inhibitors and their co-administration with insulin.