Quantitative Systems Pharmacology for Cardiorenal Drug Development: Integrating Safety and Efficacy Predictions in patients with multiple comorbidities and comedications

Recent therapeutic breakthroughs in nephrology—including SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists—have transformed the management of chronic kidney disease (CKD) and heart failure. However, their use in complex patient populations, particularly those with cardiorenal syndrome or low GFR, presents challenges in balancing efficacy and safety. Many of these therapies alter kidney sodium handling, with downstream effects on water and potassium homeostasis, raising concerns about hyperkalemia and fluid status. This talk will present case studies in applying a cardiorenal quantitative systems pharmacology (QSP) model to predict the integrated effects of therapies on both safety and efficacy endpoints. In particular, we will explore how a well-established model of sodium and fluid regulation by the kidney was expanded, calibrated, and validated to assess plasma potassium regulation, and its application to improve understanding of therapeutic interactions and optimize treatment strategies for high-risk populations.