MODELING THE PHARMACOKINETICS AND PHARMACODYNAMICS OF DEXAMETHASONE IN DEPRESSED-PATIENTS

Changes in time course effected by cortisol suppression and the relationship of these changes to the plasma dexamethasone concentration of suppressor and nonsuppressor patients are described in this report on a combined pharmacokinetic-pharmacodynamic model. Thirteen depressed patients (8 suppressors and 5 nonsuppressors) received an intravenous dose (1.5 mg) of dexamethasone. The drug-induced effect changes are found to lag behind, in time, the plasma drug level changes. To accurately relate the temporal relationship of effect changes to plasma dexamethasone levels, a pharmacodynamic model (sigmoid-E(max)) was combined with a pharmacokinetic model that incorporated an effect compartment. The magnitude of the time-lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma dexamethasone levels (t1/2k(eo)). The t1/2k(eo) of the nonsuppressing group was about 50 % of that of the suppressing group, indicating that for a given plasma level the onset and termination of effect for the nonsuppressing group is about two times more rapid than for the suppressing group. Moreover, the model can estimate the effect-site concentration that causes one-half of the maximal predicted effect (EC50), a measure of an individual's sensitivity to dexamethasone. The receptor sensitivity (as determined from the EC50 ratio) of the suppressing group was about twice that of the nonsuppressing group.