Models for the pharmacokinetics and pharmacodynamics of insulin in alloxan-induced diabetic dogs

Abstract

A combined pharmacokinetic/pharmacodynamic model was proposed to describe the pharmacokinetics of intravenously administered regular insulin (0.55 units/kg) in alloxan-induced diabetic dogs. Serum insulin concentrations were described by either a one- or two-compartment open model, in which a hypothetical effect compartment was linked to the central pharmacokinetic compartment, or in which the effect compartment was linked to the peripheral compartment. Response, as measured by percent change in glucose concentration from adjusted basal plasma concentrations, was modeled using the sigmoidal Emax effect model, a linear effects model, a log-linear effects model, and a gamma-linear effects model, using the insulin pharmacokinetic parameters to describe the amount in the hypothetical effect compartment. The results indicated that insulin pharmacokinetics are usually described by a two-compartment open model. Response to insulin was predicted more accurately in half of the dogs using the gamma-linear effects model in which the effect compartment was linked to the central compartment. In the other half of the dogs the best model was the sigmoidal Emax model in which the effect compartment was linked to the central pharmacokinetic compartment. The parameters in the latter model were correlated with each other and the confidence limits of the parameter estimates were larger than the parameters of the gamma-linear effects model. These models should be further investigated, but may offer an alternative method for distinguishing rapid insulin metabolism from insulin resistance.