A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses : The antiemetic effect of ondansetron

This paper presents and illustrates methodology for specifying, estimating, and evaluating a predictive model for repeated measures time-to-event responses. The illustrative example specifies a model of the antiemetic effect vs. concentration relationship for the 5-HT3 antagonist ondansetron in the human ipecac model for emesis. A key part of this model is a time-dependent log hazard function for emesis that is increased by ipecac administration and decreased by ondansetron concentration. The model is fit using an approximate maximum likelihood method. The data consist of the time free of emeses and, for those individuals with emetic episodes, the time(s) of the episode(s). Model evaluation is accomplished using residual plots adapted to time-to-event data and a "posterior predictive check" wherein observed data statistics are compared to those obtained from data simulated from the fitted model. The ondansetron concentration required to obtain a 50% reduction in the hazard of emesis is estimated to be 1.4 +/- 0.2 ng/ml, and the rate constant for elimination of ipecac-induced hazard is 1.5 +/- 0.2 hr-1.