Intra- and interindividual variations in steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients treated chronically with various doses of risperidone.

The intra- and interindividual variability in apparent steady-state plasma levels of risperidone (RSP) and its metabolite 9-hydroxyrisperidone (9-OHRSP) in schizophrenic patients was investigated. Patients (n = 46, age 26.4 +/- 5.3 years) with diagnosed schizophrenia were treated with a fixed daily oral dose of RSP (1-12 mg/d). The steady-state plasma samples from these patients were collected over a period of 5 years and a total of 549 visits. Plasma concentrations of RSP and 9-OHRSP were determined using a highly sensitive and specific LC-MS-MS method with a detection limit of 0.1 ng/mL. All plasma samples had measurable amounts of 9-OHRSP; however, RSP was nondetectable (<0.1 ng/mL) in 18% of the plasma samples. 9-OHRSP levels were, on average, approximately 22 times higher than those of RSP. The plasma levels of RSP and 9-OHRSP varied widely among patients receiving similar doses of RSP, and the intra- and interindividual variations of RSP and 9-OHRSP plasma levels were found to be large. The data indicated that there was no significant change in the steady-state levels of either RSP or 9-OHRSP during the treatment period. Similarly, the dose-normalized concentration did not vary significantly during the treatment period or with the administered dose. The absence of RSP in many plasma samples (<0.1 ng/mL) and presence of 9-OHRSP at severalfold higher concentrations than RSP indicate that measuring plasma levels of RSP alone may lead to erroneous interpretation in plasma level monitoring studies. The current data support the fact that it is important to measure steady-state levels of total active moiety by analyzing both RSP and 9-OHRSP for plasma drug monitoring.