Determination of Plasma Concentration Reference Ranges for Risperidone and Paliperidone.

Schizophrenia is a common disease managed by a range of interventions, with the primary treatment being antipsychotic medications (APS). Inadequate response, lack of adherence, and/or adverse events often prevent optimal therapeutic effects or therapeutic efficiency. Monitoring APS plasma concentrations can be used together with a full clinical evaluation to help improve patient care or offer better treatment options for the patient. To enable interpretation of individual risperidone and paliperidone plasma concentrations, we developed "reference ranges," which consider the expected variability in plasma concentrations between subjects across the population, rather than representing a "therapeutic range" that relates to efficacy and/or safety outcomes. The reference ranges were derived from population pharmacokinetic models, which varied based upon administration route, dose, and time after dose. Good agreement between the proposed reference ranges and external data was obtained through graphical and numerical evaluations, indicating they could be reliably used in clinical practice.

Optimizing Antipsychotic Patient Management Using Population Pharmacokinetic Models and Point-of-Care Testing.

Schizophrenia is a common disease, characterized by progressive functional decline exacerbated by psychotic relapses that often result from a lack of full adherence to antipsychotic (APS) medication. Although atypical APS medications do not have clear therapeutic windows, as generally required for therapeutic drug monitoring (TDM), measuring APS plasma levels in the context of a population expected range at the point-of-care (POC) may provide valuable clinical insights for differentiating lack of efficacy from a lack of adherence to medication.

Pharmacokinetic profile of long-acting injectable risperidone at steady-state: comparison with oral administration.

The single dose pharmacokinetic profiles of long-acting injectable (LAI) risperidone and oral risperidone were extrapolated to steady-state. Plasma concentrations of the active moiety (unchanged risperidone + 9-hydroxy-risperidone) were measured by radioimmunoassay up to 72 h after a single oral 1 mg dose of risperidone in healthy volunteers (n = 12), and up to 84 days after a single intramuscular injection of 50 mg LAI risperidone in schizophrenic patients (n = 26). These data were projected to multiple dose regimens (4 mg/day for the oral formulation and 50 mg every 2 weeks for LAI formulation) using the software package WinNonlin, and average steady-state pharmacokinetic profiles were predicted. The most interesting results, obtained at steady-state, were a lower predicted peak plasma level (46 vs. 62 ng/ml) and a lower predicted degree of fluctuation between Cssmax and Cssmin (53 vs 145%) with LAI compared to oral administration, which is in line with actual steady state data on LAI risperidone. In conclusion, the pharmacokinetic profile of LAI risperidone administered every 2 weeks ensures a steady-state profile with concentrations falling in the interval observed with an equivalent oral dose but with lower and less fluctuations (i.e. 1/2 weeks vs 1/day).

Validated method for the determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography-tandem mass spectrometry.

Since the first entry of risperidone on to the market in the early 1990s, investigation of the pharmacokinetic behaviour of the compound for which the availability of a bioanalytical method was a condition sine qua non, has received considerable attention. Most of the published methods, however, did not reach the level of sensitivity and selectivity which can be obtained today since the evolution of liquid chromatography-tandem mass spectrometry (LC-MS-MS) towards a routine technique in the bioanalytical laboratory. Therefore, we developed and validated a new LC-MS-MS method for the determination of risperidone and its active metabolite 9-hydroxyrisperidone in human plasma. This paper describes in detail the bioanalytical procedure and summarizes the validation results obtained. In addition, it focuses on the pitfalls one might encounter when developing similar assays. Despite the particular physicochemical characteristics of risperidone and 9-hydroxyrisperidone, the LC-MS-MS method enabled the quantification of both compounds down to 0.1 ng/ml. The method uses a sample preparation step by solid-phase extraction at pH 6 using a mixed-mode phase. In a short chromatographic run, separation of 9-hydroxyrisperidone from the minor metabolite 7-hydroxyrisperidone is achieved. Detection takes place by (turbo)ionspray tandem mass spectrometry in the positive ion mode. The validated concentration range is from 0.100 to 250 ng/ml, using 500 microliter of sample, with accuracy (bias) and precision (coefficient of variation) being below 15%. Although new developments in equipment will allow us to further improve and speed up the method, the assay reported can be used as a routine method to support a wide range of pharmacokinetic studies.

Comparison of alfentanil, fentanyl and sufentanil for total intravenous anaesthesia with propofol in patients undergoing coronary artery bypass surgery.

We have studied the pharmacokinetics and pharmacodynamics of alfentanil, fentanyl and sufentanil together with propofol in patients undergoing coronary artery bypass graft surgery (CABG). Sixty patients (age 40-73 yr, 56 male) were assigned randomly to receive alfentanil, fentanyl or sufentanil and propofol. Plasma concentrations of these drugs and times for the plasma concentration to decrease by 50% (t50) and 80% (t80) after cessation of the infusion were determined. Times were recorded to awakening and tracheal extubation. Total dose and plasma concentrations of propofol were similar in all groups. Mean total doses of alfentanil, fentanyl and sufentanil were 443, 45 and 4.4 micrograms kg-1, respectively. Time to awakening did not differ significantly. In patients receiving fentanyl, the trachea was extubated on average 2 h later than in those receiving sufentanil and 3 h later than in those receiving alfentanil (P < 0.05). The t80 of fentanyl was longer (P < 0.05) than that of alfentanil or sufentanil, and there was a linear correlation between the t80 of the opioid and the time to tracheal extubation (r = 0.51; P < 0.01). However, the t50 values for these opioids were similar and did not correlate with recovery time. In conclusion, patients undergoing CABG and who were anaesthetized with fentanyl and propofol needed mechanical ventilatory support for a significantly longer time than those receiving alfentanil or sufentanil and propofol. On the basis of the interindividual variation observed, the time to tracheal extubation was most predictable in patients receiving alfentanil and most variable in patients receiving fentanyl, a finding which may be important if the patients are transferred to a step-down unit on the evening of the operation.