Pharmacodynamic modeling of digoxin-induced bradycardia

Digoxin-induced bradycardia in dogs was used to evaluate several pharmacodynamic models. Digoxin plasma concentrations and response were monitored in beagle dogs administered either 0.05 or 0.025 mg/kg of digoxin iv as an infusion over 5 min. The models investigated were the linking model, the linear model, the effect compartment model, and the inhibitory model. Regression procedures for investigating the effect compartment model were conducted with Emax (the maximal response, where response was the percentage decrease in heart rate) as a variable with an upper bound of 100%, with a constant value of 100%, or alternately with a constant value equal to the maximal observed response. Based on statistical criteria the effect model using Emax as a variable was found to be the best model for describing digoxin-induced bradycardia. For the effect compartment model, CPss(50) (concentration at steady state that will produce 50% of the maximal response) ranged from 3.8-9.8 ng/ml; delta (exponent describing the steepness of the concentration-response relationship) ranged from 0.6-7.1. The implication of these models in understanding concentration-effect relationships are discussed.