Pharmacokinetic-pharmacodynamic model for educational simulations

Abstract

Pharmacokinetic-pharmacodynamic (PK-PD) models play an important role in educational simulations. The parameters of PK-PD models described in the scientific literature are obtained from studies in which the drug concentrations and the drug-effect data are measured simultaneously. Simultaneous PK-PD studies cannot be expected to incorporate all possible combinations of drugs and patient physiology that are desired for educational simulations. To solve this problem, we elaborate on the traditional simultaneous PK-PD model, creating a new model that accepts parameter data from different, more readily available, nonsimultaneous pharmacologic studies. These data are incorporated in the model using a novel estimation procedure for the parameters kc0 and EC50. A sensitivity analysis of the parameter estimation procedure confirms that the time of peak effect following a bolus and the dose-response curve are accurately reflected by the new model. It also demonstrates how inconsistencies among the different parameter sets affect simulation of the recovery phase. The model is extended to incorporate any monotonic parametric or nonparametric dose-response curve. For the neuromuscular relaxant vecuronium, we demonstrate that data from different pharmacologic studies are available, and that the described estimation procedure leads to parameter estimates that are within the standard deviations of the parameters determined in a simultaneous PK-PD study.