Rational Design of Glucose‐Responsive Insulin Using Pharmacokinetic Modeling

Abstract

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, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The 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 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing.

Connecting Rodent and Human Pharmacokinetic Models for the Design and Translation of Glucose-Responsive Insulin

“…Alarmingly, three-quarters of physicians have reported nonadherence to the prescribed regimen in their patients, which can be attributed to both the uncomfortable and the timeconsuming nature of the traditional therapy (3). The intrinsic drawbacks of an open-loop therapy are further highlighted by factors such as interindividual variations, the lag between blood glucose measurement and insulin administration, delayed absorption, and the conservatism in dosing as a result of hypoglycemia concerns (4,5). Resnick et al (6) estimated that the desired glycemic control was not achieved by one-half of the patients with diabetes surveyed.…”

“…Specifically, GRI models were not pieced together with the underlying insulin-glucose-glucagon metabolism (13,14). Our previous work (5) established the first framework that linked GRI designs to their therapeutic effectiveness through pharmacokinetic modeling of patients with T1DM.…”

The future of insulin therapy

“…But even without this lag time it will be difficult to achieve both fast release and fast binding of insulin. Mathematical models showed a very small range for forward and reverse rate constants for the transformation of inactive (insulinbinding) GRI to active (insulin-releasing) GRI for achieving tight blood glucose control [38]. Designing a GRI showing this optimal range of rate constants will be a major challenge, in particular when considering inter-patient variability.…”

“…The ideal GRI would be able to replace both prandial and basal insulin needs. Patients would just have to ''fill up" the body pool of GRI from time to time and insulin would always be released when blood glucose levels rise [38]. In view of the many challenges to develop some glucose responsiveness at all, it seems doubtful, though, that a basal GRI with a long half-life will be released fast enough to cover prandial insulin needs or that a prandial GRI with a short half-life will act as basal insulin without the need of several injections per day.…”

The promising future of insulin therapy in diabetes mellitus

“…Despite these major advancements, there are currently no approved insulin therapies whose bioactivity is regulated by blood glucose levels. Major challenges in the engineering of these novel therapies include ensuring biocompatibility, particle stability, adequate insulin response rate, and nontoxic carrier materials (32)(33)(34).…”