INFLUENCE OF AGE, RENAL AND LIVER IMPAIRMENT ON THE PHARMACOKINETICS OF RISPERIDONE IN MAN

The pharmacokinetics of the antipsychotic agent risperidone were inves tigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparativ e trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone an d the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma pro tein binding were observed in hepatic and renal disease, whereas the p rotein binding was not influenced by aging. The inter-individual varia bility in plasma concentrations of the active moiety was much less tha n the variability in plasma concentrations of risperidone. Three out o f six subjects, behaving like poor metabolizers, were on medication (t hiethylperazine, amitriptyline, metoprolol) that may inhibit risperido ne metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokine tics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced i n renal disease patients. The elimination rate and clearance of 9-hydr oxy-risperidone was reduced in elderly and renal disease patients beca use of a diminished creatinine clearance. The CL(oral) of the active m oiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addi tion, the t(1/2) of the active moiety was prolonged (19 h in young sub jects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients wit h renal disease. In cirrhotic patients, the single-dose pharmacokineti cs were comparable to those in healthy young subjects.