A. Van Peer, R. Gasparini, R. Woestenborghs, J. Heykants
Dept. of Pharmacokinetics and Drug Metabolism, Janssen Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium
Only limited doses of the antipsychotic risperidone can be tolerated when given acutely. Single-dose pharmacokinetic studies were restricted to oral doses of 2 mg in healthy volunteers and 4 mg in psychotic patients. After a short but gradual dose-titration period, doses of 1 to 16 mg daily were evaluated in the clinical efficacy trials. The blood sample collected at the end of those clinical trials provided the possibility to evaluate risperidone’s dose-proportionality.
Data were pooled from 57 healthy volunteers and 53 psychotic patients of six formal kinetic studies and from 599 psychotic patients of two Phase-III clinical trials. A subset of volunteers from the formal kinetic studies was phenotyped for their dextromethorphan metabolic status. Plasma concentrations of risperidone and the active moiety of risperidone plus its equiactive metabolite 9-hydroxy-risperidone were assayed by two radioimmunoassay procedures.
The drug plasma concentration-time profiles in the formal kinetic studies were subjected to a population pharmacokinetic analysis with NONMEM using one- and two-compartment models with first-order absorption and elimination in order to establish the best kinetic model. Based upon the AUC ratio of 9-hydroxy-risperidone to risperidone, subjects were considered either as extensive (EM) or poor (PM) metabolisers, and their data were separately fitted.
The population pharmacokinetic parameters were used to calculate the mean and the 95%-prediction interval of the plasma concentrations for the different dose-levels investigated in the clinical trials. Predicted and observed concentrations were found to be in good agreement, demonstrating risperidone’s dose-proportionality up to 16 mg daily. Patients were divided into three categories for age and body weight in order to screen for important effects of age or weight on the plasma levels, but no great effects were found.
Reference: PAGE 1 (1992) Abstr 897 [www.page-meeting.org/?abstract=897]
Poster: oral presentation