Summary

• The pharmacokinetics (PK) and drug interactions described below are for all oral formulations of risperidone (tablets, oral solution, and orally disintegrating tablets).
• PK studies demonstrated that RISPERDALM-TABS and RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets.¹
• Risperidone is well-absorbed. The absolute oral bioavailability of risperidone is 70%.¹
• Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.¹
• Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α₁-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces the other from plasma binding sites.¹
• Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme CYP2D6.¹
• An in vitro correlation study demonstrated that the formation of 9-hydroxyrisperidone is correlated with CYP2D6 and 3A activities.²
• Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. The apparent half-life of risperidone is 3 hours in extensive metabolizers and 20 hours in poor metabolizers.¹
• The PK of risperidone and 9-hydroxyrisperidone in children was similar to those in adults after correcting for the difference in body weight.^1,3

IN VITRO PK studies

Formation of 2 Enantiomers: (+)- and (-)-9-Hydroxyrisperidone

Yasui-Furukori et al (2001)⁴ reported that risperidone is metabolized by different cytochrome P450 (CYP) enzymes, including CYP2D6, to the active 9-hydroxyrisperidone, the major plasma metabolite. Two enantiomers, (+)- and (-)-9-hydroxyrisperidone, might be formed. The purpose of the study was to evaluate CYP2D6 and CYP3A4/CYP3A5 in the formation of two enantiomers, (+)- and (-)-9-hydroxyrisperidone, in human liver microsomes and in recombinantly expressed enzymes. The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral α₁-acid glycoprotein column. A higher formation rate was observed for (+)-9-hydroxyrisperidone than for (-)-9-hydroxyrisperidone in microsomes from 6 individual livers. Quinidine, a potent CYP2D6 inhibitor, inhibited the formation of (+)-9-hydroxyrisperidone. Ketoconazole, a CYP3A4 inhibitor, strongly inhibited the formation of (-)-9-hydroxyrisperidone. Recombinant human CYP2D6 produced only (+)-9-hydroxyrisperidone. A lower formation rate of both enantiomers was detected with expressed CYP3A4 and CYP3A5. In vivo data from 18 patients treated with risperidone indicate that the plasma concentration of the (+)-enantiomer is higher than that of the (-)-enantiomer in extensive metabolizers of CYP2D6. CYP2D6 is important in (+)-9-hydroxylation of risperidone, the major metabolic pathway in clinical conditions. CYP3A catalyzes the formation of the (-)-9-hydroxymetabolite. More studies are necessary to determine the pharmacological/toxic activity of both enantiomers.

Formation of 9-Hydroxyrisperidone and Correlation with CYP2D6 and 3A Activities

Fang et al (1999)² reported that the metabolism to 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in humans. Hydroxylation of risperidone accounts for up to 31% of the dose excreted in the urine. Several recombinant human CYP 450 isoforms were examined, including 2D6, 3A4, and 3A5. A correlation study showed that the formation of 9-hydroxyrisperidone is correlated with CYP2D6, 3A4, and 3A5 activities of 7.5, 0.4, and 0.2 pmol^-1 CYP min^-1, respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Risperidone was also incubated in the presence of these enzymes along with quinidine, a 2D6 inhibitor, or ketoconazole, a 3A4 inhibitor. Both of these agents inhibited the formation of the active metabolite from risperidone, confirming the role of CYP2D6 and 3A4 in its metabolism. The contribution of these enzymes to the metabolism of risperidone may affect potential drug-drug interactions.

PK STUDIES IN ADULT AND GERIATRIC POPULATIONS

Characterization of Risperidone and 9-Hydroxyrisperidone PK Parameters and Evaluation of the Effect of Covariates

By utilizing limited sampling from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD)⁵ and CATIE-Schizophrenia (CATIE-SZ)⁶ trials, Feng et al (2008)⁷ applied a nonlinear, mixed-effects model to simultaneously characterize risperidone and 9-hydroxyrisperidone PK parameters and evaluate the effect of covariates (age, weight, gender, smoking status, race, and concomitant medications) on these parameters.

The liquid chromatography-tandem mass spectrometry assay (LC-MS/MS) was utilized to determine risperidone and 9-hydroxyrisperidone plasma concentrations (level of detection: 0.1 ng/mL). The population PK analysis included both a base and final (covariate) model. The base model was utilized to describe plasma concentration/time profiles for both risperidone and 9-hydroxyrisperidone (1-compartment model with first-order absorption and elimination). Separately, a mixture model was incorporated to distinguish CYP2D6 polymorphisms, and estimate clearance for poor, extensive, and intermediate metabolizers. A final (covariate) model was utilized to describe the influence of fixed effects on the PK parameters.

The total number of patients receiving risperidone in the CATIE-AD and CATIE-SZ trials was 110 (mean age: 78.3 years; 52 men) and 380 (mean age: 40.6 years; 279 men), respectively. The majority of patients were Caucasian (n=328/490) or African-American (n=140/490). Daily dose ranges, along with risperidone and 9-hydroxyrisperidone plasma concentrations, are provided in Dose Range and Plasma Concentrations for Risperidone and 9-hydroxyrisperidone.

PK parameters for risperidone and 9-hydroxyrisperidone are provided in PK Parameters for Risperidone and 9-Hydroxyrisperidone (1-Compartment Mixture Model). Overall, age significantly affected 9-hydroxyrisperidone clearance (CLM). The average CLM estimates for patients aged 45 years old and 70 years old were 6.1 L/h and 4.9 L/h, respectively.

Evaluation of Clinical PK of Risperidone and 9-Hydroxyrisperidone

Zhou et al (2006)⁸ conducted an open-label study in Chinese females to evaluate the clinical PK of risperidone and 9-hydroxyrisperidone.

The 23 patients were diagnosed with schizophrenia or schizophreniform disorders according to the Chinese Criteria of Mental Disorders with reference to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Concomitant use of drugs known to inhibit or induce CYP2D6 or CYP3A4 excluded patients from participating in the study. The dose titration schedule was of 0.5 mg twice daily for 2 days, 1 mg twice daily for 5 days, 2 mg twice daily for 7 days, followed by 2 mg once daily for 1 day. A final dose was given on day 15 following an overnight fast. Subsequent serial blood samples were drawn before the final dose and at 0.5, 1.25, 2, 3, 4, 6, 8, 12, 24 and 48 hours after the final dose. Steady-state was validated with trough plasma concentrations drawn on days 13 and 14.

A total of 23 patients (age: 28.3±9.1 years; body mass index: 23.0±3.1 kg/m²) in the risperidone group completed the study. All patients were determined as extensive or medium metabolizers of CYP2D6 by phenotyping. The results of the study show that trough plasma concentrations of risperidone and its metabolite, 9-hydroxyrisperidone, on days 12, 14, and 15 were not significantly different (P>0.05), indicating that steady-state concentrations of risperidone and its metabolite were achieved. The PK parameters of risperidone were shown to vary among patients. The results of the parameters are summarized in Table: Main Multiple Dose PK Parameters of Risperidone and 9-Hydroxyrisperidone. Serum prolactin changes were observed but there was no correlation between serum prolactin concentration and the concentration of risperidone, 9-hydroxyrisperidone, or the active moiety.

PK STUDIES IN PEDIATRIC and ADOLESCENT POPULATIONS

Risperidone Therapeutic Reference Range and Dose-Concentration Relationship in Children and Adolescents with Psychotic Disorders

Taurines R et al (2022)⁹ used therapeutic drug monitoring (TDM) to determine the therapeutic reference range of risperidone and the relationship between the dose of risperidone and serum concentration of its active moiety (risperidone + 9-hydroxyrisperidone) in children and adolescents with psychotic disorders such as schizophrenia.

Sixty-four patients (mean age: 15.6 years) received a mean risperidone dose of 3.9 mg (range, 1-8) daily. Of them, 80% received ≥1 concomitant psychotropic medication, including 6 patients who received concomitant CYP2D6 inhibitors (mainly fluoxetine). The mean serum concentration and dose-corrected concentration-to-dose (C/D) ratio of the active moiety was 32.2 ng/mL (interquartile range [IQR], 17.0-43.8) and 9.2 (ng/mL)/(mg/day) (range, 2.3-29.3), respectively. There was a significant positive correlation between the daily risperidone dose and active moiety serum concentration (r_s=0.49; P=0.001); dose differences explained 24% of concentration variations. Serum concentrations of risperidone and 9-hydroxyrisperidone as well as their ratio were significantly affected by concomitant CYP2D6 inhibitors, manifesting as an increased amount of parent substance and decreased amount of metabolite present in the background of concomitant CYP2D6 inhibitors.

The therapeutic reference range of risperidone in adults is 20-60 ng/mL. The active moiety serum concentration was below this range for 20 (31.3%) patients, above this range for 8 (12.5%) patients, and within this range for 36 (56.3%) patients. The active moiety serum concentration was higher than average in patients with extrapyramidal symptoms. With these patients in consideration, the upper limit of the therapeutic reference range of risperidone in children and adolescents was estimated at 33 ng/mL. The lower limit was estimated at 9 ng/mL.

Population PK Analysis in Children, Adolescents, and Adults

Thyssen et al (2010)³ investigated the PK of oral risperidone in children, adolescents, and adults, and the population PK in pediatric and adult patients.

Nine clinical studies were included in the population PK analysis using nonlinear mixed-effects modeling software (NONMEM^®) on a pooled database through noncompartmental analysis (pediatric phase 1 study; n=24) and population PK analysis). The concomitant use of biperiden (n=18), valproate (n=15), sertraline (n=7), fluoxetine (n=4), paroxetine (n=3), citalopram (n=3), and venlafaxine (n=2) was analyzed for possible influences on the CYP450 enzyme system and subsequent effect on risperidone and olanzapine concentrations.

After correcting the doses for body weight, PK analysis showed that plasma exposure was comparable between children and adolescents, and similar to that of adults.

Effect of Age and Gender on Risperidone and Olanzapine Plasma Concentrations and Concentration-to-Dose Ratios

Aichhorn et al (2007)¹⁰ conducted a retrospective study to determine the effect of age and gender on risperidone and olanzapine plasma concentrations and C/D ratios in 162 Caucasian children and adolescents.

Fasting morning blood samples were obtained approximately 12 hours following the prior evening's 8:00 PM dose to determine steady-state drug concentrations (maintenance dose received for >7 days). The concomitant use of biperiden (n=18), valproate (n=15), sertraline (n=7), fluoxetine (n=4), paroxetine (n=3), citalopram (n=3), and venlafaxine (n=2) was analyzed for possible influences on the CYP450 enzyme system and subsequent effect on risperidone and olanzapine concentrations. The LC-MS/MS was utilized to determine risperidone, 9-hydroxyrisperidone, and olanzapine plasma concentrations (level of detection: 0.5 ng/mL; level of quantification: 1 ng/mL).

The effect of age on risperidone and olanzapine dose, plasma concentration, and C/D ratios was assessed by comparing 2 age groups: 10-18 years (children/adolescents) and 19-45 years (adults). Results for risperidone can be found in the Table: Effect of Age and Gender on Risperidone Dose, Plasma Concentration, and C/D Ratios. Compared to adults, children and adolescents were prescribed significantly lower doses of risperidone and had significantly lower total plasma concentrations (C_total). The C/D ratios for total (risperidone + 9-hydroxyrisperidone), risperidone, and 9-hydroxyrisperidone plasma concentrations were almost identical for both age groups and were unaffected by weight adjustments. While gender had no significant effect on dose, concentration, or C/D ratios in adults, adolescent females had significantly higher mean total plasma levels and C_total/D ratios compared to males, while receiving similar doses (3.46 mg/day vs 3.12 mg/day, respectively; P=0.544) (Effect of Age and Gender on Risperidone Dose, Plasma Concentration, and C/D Ratios). For risperidone, valproate coadministration had a significant effect on plasma concentrations irrespective of age (55% higher C_total/D ratios).

PK Parameters of Risperidone and Its Enantiomers in Saliva and Plasma

Aman et al (2007)¹¹ conducted an open-label study in pediatric patients with psychiatric or neurodevelopmental disorders to determine the PK parameters of risperidone and its enantiomers in both saliva and plasma.

Nineteen patients (mean age: 10.1 years) receiving a stable twice daily dose of risperidone for ≥4 weeks were entered into the study. Concomitant use of the following medications was prohibited: anti-human immunodeficiency virus medications, azole antifungals, calcium channel blockers, carbamazepine, cimetidine, macrolides, phenytoin, propoxyphene, rifampin, and tramadol. Trough blood levels and predose saliva levels were determined through fasting morning samples obtained approximately 12 hours following the prior evening's 8:00 PM dose. At 8:00 in the morning, the morning dose of risperidone was administered with 100 mL of water. Additional blood and saliva samples were obtained at 1, 2, 4, and 7 hours postdose. The chiral LC-MS/MS was utilized to determine risperidone and 9-hydroxyrisperidone enantiomer levels in both plasma (lower limit of quantitation: 0.2 ng/mL) and saliva (lower limit of quantitation: 0.4 ng/mL).

The PK parameters for risperidone and its enantiomers are found in Mean PK Parameters of Risperidone and Its Enantiomers in Plasma and Saliva. Interindividual risperidone and enantiomer concentrations greatly varied. Mean plasma maximum concentration (C_max) and area under the concentration-time curve (AUC) for (+)-9-hydroxyrisperidone were approximately 2.8- and 2.5-fold higher, respectively, than for (-)-9-hydroxyrisperidone, while enantiomer concentrations and AUC appeared similar in saliva. Results from the logarithmic regression model, based on predose samples only, showed that the log risperidone saliva concentration=–0.100 + 0.594 • log plasma concentration [R²=0.93 (Spearman)].

PK of Risperidone and its Active Metabolites (+) and (-) 9-Hydroxyrisperidone in Pediatric Patients

Vinks et al (2006)¹² discussed the results of an open-label, phase 1 trial looking at the PK of risperidone and its active metabolites (+) and (-) 9-hydroxyrisperidone in pediatric patients. The study included 19 patients of mean age 9.9 years (range, 4.2-15.9). Blood samples were drawn at steady-state, predose, 1, 2, 4, and 7 hours postdose.

Mean risperidone C_max concentrations were 15.9+22.2 mcg/L and predose troughs were 8.3+20.4 mcg/L. Predose concentrations were 6.6+4.4 mcg/L for (+) 9-hydroxyrisperidone and 3.81+2.39 mcg/L for (-) 9-hydroxyrisperidone, respectively. The PK parameters are listed in PK Parameters.

SINGLE-DOSE PK STUDIES

Factors Influencing the Concentrations of Risperidone and 9-Hydroxyrisperidone in Patients Receiving Immediate-Release Risperidone

Guo Z et al (2023)¹³ retrospectively evaluated TDM data from psychiatric outpatients receiving immediate-release risperidone between March 2018 and February 2020 to identify the factors affecting the serum concentrations of risperidone and 9-hydroxyrisperidone.

Three hundred and ninety-nine patients (98.25% aged 18-64 years) received 1-14 mg of risperidone, of whom >95% received ≥1 (mean: 3.18) concomitant medications including central anticholinergics, antischizophrenics, antiepileptics/mood stabilizers, benzodiazepines, and selective serotonin reuptake inhibitors (SSRIs). Patients were most commonly diagnosed with schizophrenia (46.87%) and bipolar disorder (25.31%), and 8.77% of them had abnormal liver function.

There was a positive correlation between the daily dose of risperidone and serum concentrations of active moiety and 9-hydroxyrisperidone (r²=0.244). PK parameters for additional subgroups are summarized in Table: Impact of Age, Sex, Formulation, and Comorbidities on Risperidone Daily Dose, Concentration of Active Moiety, C/D, and MRP.

With the combined use of trihexyphenidyl, olanzapine, clozapine, fluvoxamine, oxazepam, metoprolol, or propranolol, patients showed higher concentrations of serum risperidone +
9‐hydroxyrisperidone compared to those without comedication. After dose corrections, only patients receiving fluvoxamine maintained a statistically significant difference in C/D (10.15±4.52 vs 6.58±3.52 [ng/ml]/[mg/day], P<0.01). The ratio of serum concentrations of 9‐hydroxyrisperidone and risperidone (MRP) of combined fluvoxamine or buspirone (1.54±1.68, P<0.001; 2.32±2.28, P<0.05) was significantly lower compared to risperidone monotherapy (5.91±7.61), indicating a partial reduction in drug metabolism and conversion.

Influence of Age, Renal, and Liver Impairment

Snoeck et al (1995)¹⁴ discusses the influence of age, as well as renal and liver impairment, on the PK of risperidone and the active moiety, 9-hydroxyrisperidone. A single oral 1 mg dose was administered to fasting patients.

Plasma and urine concentration of risperidone and 9-hydroxyrisperidone were measured by radioimmunoassay. The plasma protein binding of both risperidone and the active moiety were uninfluenced by age. Minimal changes in plasma protein binding were observed in hepatic and renal disease. The PK of risperidone in elderly were comparable to those in young patients, whereas the oral clearance of 9-hydroxyrisperidone was reduced by approximately 30%. The half-life of the active moiety was prolonged by 19 hours in young patients vs 25 hours in elderly patients and patients with renal disease. The oral clearance of 9-hydroxyrisperidone was reduced by approximately 50% in patients with renal disease. In patients with cirrhosis, the single-dose PK was comparable to that of the young healthy population. Based on the PK of the active moiety, the authors recommend a dose reduction and a cautious dose titration in the elderly and in patients with renal disease.

Evaluation of Absorption, Metabolism, and Excretion of Risperidone in 3 Healthy Males

Mannens et al (1993)¹⁵ evaluated the absorption, metabolism, and excretion of risperidone in 3 healthy males.

One week after a single oral dose of 1 mg [14C] risperidone, 70% of the administered radioactivity was recovered in the urine and 14% in the feces. Unchanged risperidone was excreted in the urine and accounted for 30%, 11%, and 4% of the administered dose in poor, intermediate, and extensive metabolizers of debrisoquine, respectively. Alicyclic hydroxylation at the 9-position of the tetrahydro-4H-pyrido[1,2-a]-pyrimidin-4-one moiety was the primary metabolic pathway. The active metabolite 9-hydroxyrisperidone accounted for 8%, 22%, and 32% of the administered dose in the urine of the poor, intermediate, and extensive metabolizers, respectively. Oxidative N-dealkylation at the piperidine nitrogen, whether or not in combination with the 9-hydroxylation, accounted for 10-13% of the dose. In methanolic extracts of feces, risperidone, benzisoxazole-opened risperidone, and hydroxylated metabolites were detected. 9-hydroxyrisperidone was the primary plasma metabolite. The sum of risperidone and 9-hydroxyrisperidone represented the largest part of the plasma radioactivity in all 3 people. Although the debrisoquine-type genetic polymorphism plays a distinct role in the metabolism of risperidone, the PK of the active fraction (ie, risperidone plus 9-hydroxyrisperidone) remained similar among the 3 people.

OTHER RELEVANT LITERATURE

Articles discussing dosing and plasma concentration correlations,^16-18 postmortem redistribution,^19,20 and quantitation^21-23 and extraction efficiencies²⁴ of psychiatric drugs including risperidone have been referenced for your convenience.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 June 2024.