Modelling of the pharmacodynamics and pharmacodynamic interactions of CNS active drugs

The pharmacodynamics and pharmacodynamic interactions of benzodiazepines have been determined using amplitudes in the 12-30 Hz frequency band of the EEG as a measure of the pharmacological response. Following the administration of a single intravenous dose, plasma concentration and pharmacological effect versus time profiles were determined and subjected to simultaneous pharmacokinetic-pharmacodynamic modelling to derive individual concentration EEG effect relationships. For flunitrazepam, midazolam, oxazepam and clobazam the concentration EEG effect relationships could be characterized on basis of the sigmoid Emax model. The values of the EC50 differed widely. A close correlation between the value of the EC50 and the affinity to the nanomolar benzodiazepine receptor in vitro was observed. For midazolam, bretazenil, flumazenil and Ro 19-4603 in addition to differences in potency also widely different values of the Emax were observed, which are in agreement with the known pharmacological properties of these compounds. The pharmacodynamic interaction between midazolam and flumazenil was characterized both under steady-state and non steady-state conditions. It was found that the effects of combined treatment with these drugs can be described and predicted on the basis of a competitive interaction model. The findings of these studies demonstrate that on the basis of an integrated pharmacokinetic-pharmacodynamic approach, important information on the pharmacodynamics and pharmacodynamic interactions of CNS active drugs can be obtained.