PK/PD modelling of glucose-insulin-glucagon dynamics in healthy dogs after a subcutaneous bolus administration of native glucagon or a novel glucagon analogue

Objective We aim to develop a simulation model of the complex glucose-insulin-glucagon dynamics based on physiology and data. Furthermore, we compare pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of marketed reconstituted glucagon with a stable liquid glucagon analogue invented by Zealand Pharma A/S.

Research Design and Methods We expanded a physiological model of endogenous glucose production with multiplicative effects of insulin and glucagon and combined it with the Hovorka glucoregulatory model. We used a Bayesian framework to perform multidimensional MAP estimation of model parameters given priors reported in the literature.

We used profile likelihood analysis to investigate parameter identifiability and reduce the number of model variables. We estimated model parameters in pre-clinical data from one cross-over study with a total of 20 experiments in five dogs. The dogs received two subcutaneous (SC) bolus injections of low and high doses of glucagon and ZP-GA-1 (20 and 120 nmol/kg).

Results We report posterior probability distributions and correlations for all identifiable model parameters. Based on visual inspection and residual analysis, the PD model described data satisfactorily for both glucagon and the analogue. Parameter estimates of the PD model were not significantly different between the two compounds.

Conclusions The new PK/PD model enables simulations of the glucose-insulin-glucagon dynamics after a SC bolus of glucagon or glucagon analogue. The novel glucagon analogue by Zealand Pharma A/S shows PK and PD characteristics similar to marketed glucagon.