Model‐Based Interspecies Scaling of Glucose Homeostasis

Abstract

Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species‐specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.

An organ-based multi-level model for glucose homeostasis: organ distributions, timing, and impact of blood flow

“…In the introduction, we mentioned the now classical nonlinear mixed effects models describing plasma levels of glucose and insulin (Silber et al 2007; Silber et al 2010; Jauslin et al 2007). These models have since these early publications been used to scale data between pre-clinical data from animals to clinical human data for glucose and insulin concentrations (Alskär et al 2017), and to describe cross-talk with more long-term processes, such as disease development in mice (Choy et al 2016) and dynamics of HbA1c (Kjellsson et al 2013; Møller et al 2013). Glucose homeostasis-centered models, focusing on the glucose-insulin interplay, lie at the heart of mathematical models developed for type 1 diabetes, e.g.…”

Mathematical Modeling for the Physiological and Clinical Investigation of Glucose Homeostasis and Diabetes

“…Simple models were used for insulin secretion and its increase after glucose ingestion; in the model on intravenous glucose data, first-phase insulin secretion was represented only in healthy subjects and omitted in T2D patients. Extensions of these models included the description of circadian rhythms [based on 24-h glucose and insulin profiles, (Jauslin et al, 2011)], glucagon kinetics and glucose production dependence from glucose, insulin and glucagon [using meal tests with glucagon measurement, (Schneck et al, 2013)], gastric emptying and glucose absorption [using paracetamol, (Alskär et al, 2016)], and scaling factors to account for interspecies differences (Alskär et al, 2017). These models employ empirical descriptions of their components (e.g., insulin secretion), sufficient to predict the available data adequately.…”

A Model‐Informed Drug Discovery and Development Strategy for the Novel Glucose‐Responsive Insulin MK‐2640 Enabled Rapid Decision Making

“…20 An integrated glucose-insulin model, as first introduced by Silber, 38 was modified to incorporate a glucose dependent MK-2640 clearance mechanism and used to describe the minipig and dog PKPD data and allometrically scaled to man. 27,28,39 This glucose-dependent clearance mechanism was assumed to be a linear change in systemic clearance between low and high glucose concentrations. Both minipig and dog models predicted a ~ 30% lower MK-2640 clearance at hyperglycemia (300 mg/dL) compared with euglycemia (75 mg/dL).…”