Pharmacokinetic-pharmacodynamic modeling of risperidone effects on electroencephalography in healthy volunteers

Rationale: CNS-active drugs produce specific electroencephalographic change s and the concentration-effect relationship of antipsychotics may be elucid ated by adopting electroencephalography (EEG)as an effect measurement tool. Objective: The purpose of the present study was to determine the concentra tion-effect relationship of risperidone by assessing the EEG effect after o ral administrations of single dose risperidone in healthy young males. Meth ods: Nine healthy male volunteers received a I mg single oral dose of rispe ridone according to a placebo controlled crossover design. Plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone were measured b y radioimmunoassay. Quantitative EEG parameters were obtained for each of f our frequency bands through spectral EEG analysis. The difference in the ab solute power in the delta frequency band for the F3 lead between risperidon e and placebo was used as a drug effect parameter. For pharmacokinetic-phar macodynamic modeling, the hypothetical effect compartment kinetically linke d to plasma by a first-order process tvas postulated. All curve fittings we re done with the nonlinear curve-fitting program NONLIN. Results: Our resul ts showed that absolute powers in delta and theta frequency bands were high er for risperidone administration than for placebo at all EEG leads, and th e maximum effects were detected at about 3 h after administration of the dr ug. The hysteresis loop was observed in the plot of plasma concentration of risperidone or sum of risperidone and 9-hydroxyrisperidone (C-p) versus EE G effect for each subject. A linear model adequately described the relation ship between the effect compartment concentrations (C-e) and EEG effects, a nd the two limbs of hysteresis in the C-p-effect plot were collapsed in the C-e-effect plot For risperidone or risperidone plus 9-hydroxyrisperidone. Conclusion: The increases of absolute power for delta and theta frequency b ands of EEG were induced by single oral administration of risperidone. The linear PK-PD model fit well with the relationship between effect compartmen t concentrations (C-e) and EEG effects of risperidone.