(634a) Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling

A Glucose Responsive Insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient’s dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, we introduce an approach to mathematically model the relevant parameter space for effective GRIs, and develop design rules for linking GRI performance to therapeutic benefit. We use well developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI to determine the desired kinetic parameters and dosing for optimal glycemic control. Our model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24-hour period. Additionally, we demonstrate our modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. Our results provide a framework for exploring the parameter space GRIs, potentially without extensive, iterative in vivo animal testing.