Figure 1.

Overview of the in silico investigation of the competitive clearance GRIs with the IM³PACT modeling platform. (A) Illustration of the glucose-responsive mechanism of MK-2640 and its variants. The carbohydrate-conjugated insulin analogs exemplified by MK-2640 (green) undergo clearance via both the intrinsic insulin receptor (IR) route as well as the additional lectin/mannose receptor (MR) route, with the latter being responsive via the competitive binding of glucose (orange). Consequently, under euglycemia (hyperglycemia), the weak (strong) competition from glucose is designed to allow a high (low) rate of MR-mediated GRI clearance, thus lowering (enhancing) its availability in circulation. Pivotal to the design concept, therefore, is a significant difference in clearance between eu- and hyperglycemia, which was not observed in the clinical clamp studies of MK-2640.¹⁸ The reversible binding processes of the GRI and glucose to MR depicted in the illustration are, respectively, represented by rate constants k_±1 and k_±3, which play important roles in the mechanistic model (eqs 1 and 2). (B) The mechanistic model almost perfectly describes the in vitro assay data of glucose-inhibited MK-2640 binding to MR²¹ but only if the Hill coefficient h_G is incorporated which represents cooperativity. (C,D) IM³PACT couples the mechanistic model of MK-2640 with a physiological model representing the full-body glucoregulation as a network of well-mixed compartments. These compartments consist of the brain, heart and lung, liver, gut, kidneys, muscle, and adipose tissues (C). By solving the equivalent system of differential equations (eqs 7–9), we are able to trace the concentrations of GRI and regular human insulin (RHI) over time, in addition to the blood glucose [G], as they are circulated and metabolized in the body of either humans or minipigs following intravenous or subcutaneous administration (D). Expt., experimental; vas., vascular; int., interstitial; and s.c., subcutaneous.