Multi-scale modeling of multi-organ systems in drug development: a case study on SGLT2 inhibitors
K. Melissa Hallow, PhD
Associate Professor, University of Georgia, School of Chemical, Materials and Biomedical Engineering, Athens, GA USA
Melissa Hallow is an Associate Professor at the University of Georgia, with joint appointments in the College of Engineering and College of Public Health. She earned her Ph.D. from the Georgia Institute of Technology and worked for several years at Novartis Pharmaceuticals before making the transition to academia at UGA. Her research group uses mathematical models of renal and cardiac physiology and pharmacology to better understand disease processes and drug mechanisms in hypertension, kidney disease, heart failure, and drug-induced kidney injury.
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This talk will describe how a multi-scale QSP model of the cardiorenal system has been used to aid in drug development decision-making, using SGLT2 inhibitors for chronic kidney disease and heart failure as a case study. SGLT2 inhibitors as a class cause an acute drop in eGFR that was initially unexplained and caused some safety concerns. QSP modeling was able to mechanistic explanation this change in eGFR, alleviating safety concerns and instead linking the eGFR response to the functional improvements. This provided a physiological basis for improved outcomes in chronic kidney disease in both diabetic and non-diabetic kidney disease, and supported the rationale for the DAPA-CKD study - the first study of SGLT inhibitors to include non-diabetics. The model also provided a mechanistic explanation for the unexpected improvements in heart failure outcomes by explaining how this mechanism of action may differentially affect blood and interstitial fluid volume. The model was able to prospectively predict changes in eGFR, UACR, and global longitudinal strain in several phase 2 and phase 3 trials. Simulations were subsequently used in health authority submissions to support dose justification and to predict long-term outcomes in a subpopulation with limited duration of follow-up.