A PHARMACOKINETIC-PHARMACODYNAMIC MODEL FOR QUANTAL RESPONSES WITH THIOPENTAL

The pharmacokinetic-pharmacodynamic model developed here characterizes the relationship between simulated plasma concentrations of thiopenta l and two dichotomous endpoints determined at induction of anesthesia: loss of voluntary motor power (clinical endpoint), and burst suppress ion of the electroencephalogram (EEG endpoint). The model incorporated data from two separate thiopental patient studies: a pharmacokinetic study with 21 males, and a pharmacodynamic study with 30 males. In the pharmacodynamic study, cumulative quantal dose-response curves for th e clinical and EEG endpoints were developed from observations made dur ing a constant-rate infusion of thiopental. Population mean parameters , derived from the bolus pharmacokinetic thiopental study, were used t o simulate concentration-time data for the 150 mg . min-1 thiopental i nfusion rate used in the dose-response study. A single biophase model incorporating the two endpoints was generated, combining the pharmacok inetic and pharmacodynamic data from the two groups. Estimates of the mean effective thiopental concentrations affecting 50% of the populati on (EC50s) for the clinical and EEG endpoints were 11.3 and 33.9 mug . ml-1, respectively. The half-time for equilibration between arterial thiopental and the effect compartment was 2.6 min. These results are i n reasonable agreement with previously described quantal concentration -response data, and with pharmacodynamic models developed for graded E EG responses. Simulation of bolus doses of thiopental with the new mod el provided ED50s for the clinical and EEG endpoints of 265 mg and 796 mg, respectively; the dose predicted to produce loss of voluntary mot or power in 90% of an adult male population was 403 mg. A model combin ing population pharmacokinetics with cumulative dose-response relation ships could prove useful in predicting dosage regimens for those drugs with responses that are categorical.