The Switch From Paliperidone Long-Acting Injectable 1- to 3-Monthly: Clinical Pharmacokinetic Evaluation in Patients With Schizophrenia (Preliminary Data).

PURPOSE/BACKGROUND: The aim of the study was a preliminary evaluation of the maintenance of clinical efficacy and tolerability of paliperidone palmitate in patients with schizophrenia during the transition phase from 1-monthly paliperidone palmitate formulation (PP1M) to PP3M, with the evaluation of plasma levels of the drug. METHODS/PROCEDURES: A prospective observational study was conducted for 13 months involving 22 outpatients, aged 18 to 66 years and clinically stabilized. Patients were affected by schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. For each patient, clinical assessment, safety and tolerability, and drug plasma level determination were performed. Clinical efficacy was assessed by Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, and Hamilton Rating Scale for Depression. During the first 4 months of the study, once-monthly paliperidone palmitate was administered, and then during the following 9 months, the 3-monthly formulation was administered. FINDINGS/RESULTS: The time course of the Brief Psychiatric Rating Scale total scores showed a statistically significant (P = 0.006) improvement from T0 to T8; Positive and Negative Symptom Scale scores showed a similar time course, with a statistically significant (P = 0.0016) reduction of the mean total score; Hamilton Rating Scale for Depression mean scores showed a statistically significant (P = 0.003) reduction with substantial maintenance of clinical stabilization of the patients. Only 1 patient dropped out after the first PP3M injection. IMPLICATIONS/CONCLUSIONS: Our preliminary data currently confirm the maintenance of clinical stability shifting from PP1M to PP3M.

Clinical response in patients treated with once-monthly paliperidone palmitate: analysis of a therapeutic drug monitoring (TDM) database.

To investigate pharmacokinetic correlates of clinical response in patients treated with once-monthly paliperidone palmitate (PP1M) injections at steady state. Plasma concentrations and dose-adjusted-plasma concentrations (C/D) of paliperidone from a naturalistic therapeutic drug monitoring (TDM) database were compared between responders and non-responders using the Clinical Global Impressions-Improvement scale (CGI-I) ratings. Analyses were based on the non-parametric Mann-Whitney U test and the Pearson Chi-squared test (χ2) with a significance level of 0.05. Subgroup analyses were performed separately in patients with schizophrenia spectrum, schizoaffective disorders and bipolar disorders. Comparing 93 responders with 80 non-responders, we detected no significant differences in the proportion of females, age, and body mass index (p's ranging 0.18-0.83); there were more smokers in the group of non-responders (p = 0.04), which also included more patients with bipolar disorders (p = 0.014). Despite the lack of differences for prescribed PP1M doses and dose intervals (p = 0.42 and p = 0.11, respectively), non-responders had higher paliperidone plasma concentrations and C/D levels (p = 0.033 and p = 0.021, respectively). Subgroup analyses did not yield differences for paliperidone plasma and C/D levels between non-responders and responders with schizophrenia spectrum (p = 0.099 and p = 0.14, respectively) and bipolar disorders (p = 0.95 and p = 0.75, respectively); dose-adjusted plasma concentrations were higher in non-responders compared to responders with schizoaffective disorders (p = 0.039), while no differences were reported for plasma levels (p = 0. 15). Our results show that paliperidone plasma concentrations over injection doses may be associated with patterns of clinical response suggesting potential utility of TDM as part of PP1M-based maintenance treatment.

Impact of age and gender on paliperidone exposure in patients after administration of long-acting injectable formulations-an observational study using blood samples from 1223 patients.

PURPOSE: Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations. METHODS: Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15-49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used. RESULTS: In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p<0.001). Compared to males, females had higher C/D ratio (+14%; p<0.001). Subsequently, older female users of once-monthly LAI intervals had 41% higher paliperidone C/D ratios compared to younger males (15.0 vs. 21.2 nM/mg; p<0.001). Compared to females aged 21-30 years, females with high age (≥70 years) had at least 105% higher paliperidone C/D ratio (p<0.001). CONCLUSION: The present study shows that older age and female gender are associated with higher paliperidone exposure than younger age and males, respectively. Particularly, older female patients (>50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.

Lack of Smoking Effects on Pharmacokinetics of Oral Paliperidone-analysis of a Naturalistic Therapeutic Drug Monitoring Sample.

INTRODUCTION: Major smoking effects have been reported for a series of psychotropic agents, mainly including substrates of CYP450 1A2, although smoking may also affect alternative metabolic pathways. To our knowledge, smoking effects on paliperidone pharmacokinetics have not been assessed yet. METHODS: We compared plasma concentrations of paliperidone as well as dose-corrected-plasma concentrations (C/D) from a naturalistic database between smokers and nonsmokers using nonparametrical tests, such as the Mann-Whitney U-test (MWU). Additionally, we compared light and heavy smokers with nonsmokers separately. RESULTS: Comparing 55 smokers with 37 nonsmokers treated with oral paliperidone, no differences in the percentage of females, age, body weight, body mass index, and daily paliperidone dose were reported (p=0.709 for χ2, p=0.26, p=0.38, p=0.67, and p=0.8 for MWU). No differences were detected in plasma concentrations or C/D values (p=0.50 and p=0.96 for MWU). Likewise, differences in daily dose, plasma concentrations, or C/D values were not significant between light smokers (n=17) and nonsmokers (p=0.61, p=0.81, and p=0.33 for MWU) or heavy smokers (n=22) and nonsmokers (p=0.874, p=0.38, and p=0.59; MWU in all cases). DISCUSSION: Paliperidone is not affected by smoking, and paliperidone dose-adjustments in smokers may not be necessary. This may be seen as an essential difference to risperidone, whose cytochrome-mediated metabolism might be affected by smoking.

Identification and Quantification of Antipsychotics in Blood Samples by LC-MS-MS: Case Reports and Data from Three Years of Routine Analysis.

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.

Field-amplified sample injection in capillary zone electrophoresis for the pharmacokinetic research of trace risperidone and its major metabolite 9-hydroxyrisperidone in beagle dogs.

This article describes a method for the simultaneous quantitation of risperidone and its major metabolite, 9-hydroxyrisperidone, in beagle dog plasma by field-amplified sample injection in capillary zone electrophoresis. The separation was carried out at 25°C in a 48 cm × 75 µm fused-silica capillary with an applied voltage of 20 kV using 60 mM NaH2 PO4 buffer (pH 3.6). The detection wavelength was 280 nm. Clean-up and preconcentration of plasma samples were conducted by 96-well formatted liquid-liquid extraction. In this study, this stacking technique provided a sensitivity enhancement of approximately 158 to 188 fold compared with the same sample without stacking. The method was suitably validated with respect to stability, specificity, linearity, lower limit of quantitation, accuracy, precision, and extraction recovery. Calibration curves exhibited good linearity (r2  > 0.995) over a wide concentration range of 2.5 to 200 ng/mL for both risperidone and 9-hydroxyrisperidone. The intra- and interday precisions at the three quality control levels were less than 11.40%. The intra- and interday accuracies ranged from 87.90 to 107.17% for risperidone and from 88.43 to 105.92% for 9-hydroxyrisperidone. All validation data were within the required limits. In conclusion, the method developed was successfully applied to pharmacokinetic studies of risperidone and 9-hydroxyrisperidone in beagle dogs.

Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes.

BACKGROUND AND OBJECTIVES: The genetic polymorphism of cytochrome P450 (CYP) 2D6 is characterized by an excessive impact on positive and adverse drug reactions to antipsychotics, such as risperidone. Consequently, the pharmacokinetics of the drug and metabolite can be substantially altered and exhibit a high variability between the different phenotypes. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model considering the CYP2D6 genetic polymorphism for risperidone and 9-hydroxyrisperidone (9-OH-RIS) taking CYP3A4 into account. Additionally, risperidone dose adjustments, which would compensate for genetically caused differences in the plasma concentrations of the active moiety (sum of risperidone and 9-OH-RIS) were calculated. METHODS: Based on available knowledge about risperidone, 9-OH-RIS, and relevant physiological changes according to different CYP2D6 phenotypes, several PBPK models were built. In addition, an initial model was further evaluated based on the plasma concentrations of risperidone and 9-OH-RIS from a single-dose study including 71 genotyped healthy volunteers treated with 1 mg of oral risperidone. RESULTS: PBPK models were able to accurately describe risperidone exposure after single-dose administration, especially in the concentration range ≥ 1 µg/L, illustrated by a minimal bias and a good precision. About 90.3% of all weighted residuals versus observed plasma concentrations ≥ 1 µg/L were in the ± 30% range. The risperidone/9-OH-RIS ratio increased progressively according to reduced CYP2D6 activity, resulting in a mean ratio of 4.96 for poor metabolizers. Simulations demonstrate that dose adjustment of the drug by - 25% for poor metabolizers and by - 10% for intermediate metabolizers results in a similar exposure to that of extensive metabolizers. Conversely, the risperidone/9-OH-RIS ratio can be used to determine the phenotype of individuals. CONCLUSION: PBPK modelling can provide a valuable tool to predict the pharmacokinetics of risperidone and 9-OH-RIS in healthy volunteers, according to the different CYP2D6 phenotypes taking CYP3A4 into account. These models are able to ultimately support decision-making regarding dose-optimization strategies, especially for subjects showing lower CYP2D6 activity.

Population Pharmacokinetics of Paliperidone Palmitate (Once-Monthly Formulation) in Japanese, Korean, and Taiwanese Patients With Schizophrenia.

The paliperidone pharmacokinetics after intramuscular administration of once-monthly paliperidone palmitate in Japanese patients were studied in 3 phase 1 studies and in 2 phase 3 studies performed in Japan, Korea, and Taiwan. These data (Japanese, n = 509; Korean, n = 31; Taiwanese, n = 47) were used to describe the paliperidone palmitate pharmacokinetics in Japanese, to compare with non-Japanese, and to validate the historical population pharmacokinetic (Pop-PK) model for paliperidone palmitate, developed using data from studies in patients with schizophrenia outside Japan. The final historical Pop-PK model, including all significant patient covariates of Japanese studies, was used to simulate paliperidone plasma concentration-time data using nonlinear mixed effects, followed by comparison with actual data. Visual predictive checks displayed considerable overlap between predicted and actual plasma concentrations; the majority of observations were within the 90% prediction interval. Japanese, Korean, and Taiwanese patients had comparable plasma concentrations. Covariate distributions demonstrated comparatively lower median body mass index in Japanese, Korean, and Taiwanese patients versus rest-of-world population. Prediction errors for the data set used for external validation were within cutoff values, confirming accuracy/precision of the model. Paliperidone pharmacokinetics were adequately predicted for Japanese studies using the historical Pop-PK model, confirming its robustness. Pharmacokinetics in Japanese, Korean, and Taiwanese patients with schizophrenia were comparable with rest-of-world population.

Influence of Kidney Function on Serum Risperidone Concentrations in Patients Treated With Risperidone.

OBJECTIVE: Risperidone is one of the most commonly prescribed antipsychotics worldwide. Its main metabolite, 9-hydroxyrisperidone (9-OH-RIS), is excreted renally. The present study examined the relationship of kidney function and serum risperidone concentrations in a large sample of risperidone-treated patients. METHODS: Serum concentrations of risperidone and its active metabolite 9-OH-RIS, as well as creatinine concentrations, from which glomerular filtration rates (GFRs) were estimated, were determined in 175 risperidone-medicated patients (75 female, 100 male). Data were collected between July 2013 and December 2016. Patients were clustered in 4 groups according to their estimated GFR (eGFR) (30-60; > 60-90; > 90-120; and > 120 mL/min/1.73 m²), and serum concentrations of risperidone and 9-OH-RIS and their sum (active moiety [AM]) were compared groupwise. Additionally, serum concentrations were correlated with kidney function. RESULTS: Dose-corrected AM and dose-corrected 9-OH-RIS concentrations were significantly higher in patients with an eGFR of 30-60 mL/min/1.73 m² than in patients with an eGFR > 90-120 mL/min/1.73 m² (P < .001 for dose-corrected AM and P = .001 for dose-corrected 9-OH-RIS) or > 120 mL/min/1.73 m² (P = .036 and .021, respectively). Dose-corrected AM levels were more than doubled in the 30-60 mL/min/1.73 m² group compared to the > 90-120 mL/min/1.73 m² group (mean ± SD = 22.2 ± 14.0 [ng/mL]/[mg/d] vs 10.1 ± 7.7 [ng/mL]/[mg/d]). In the total group, eGFR and dose-corrected 9-OH-RIS and dose-corrected AM were weakly but statistically significantly correlated (Spearman rank correlation coefficient [Rs] = -0.2, P = .004, and Rs = -0.17, P = .01, respectively). CONCLUSIONS: Kidney function is an important determinant of risperidone clearance. These data suggest reducing the risperidone dose by 50% in patients with a GFR below 60 mL/min.

Metabolism of risperidone by CYP2D6 and the presence of drug-induced dopamine supersensitivity psychosis in patients with schizophrenia.

High-dose antipsychotic(s) can induce dopamine supersensitivity psychosis in schizophrenia patients. The precise relationship between a drug's blood concentration and the occurrence of dopamine supersensitivity psychosis has not been established. We divided 36 patients with schizophrenia who had undergone treatment mainly with risperidone into two groups: one with normal metabolizing activity of CYP2D6 (n = 15), and the other with lower activity of its variant, CYP2D6*10 (n = 21). The patients' blood concentrations of risperidone and 9-OH-risperidone were measured, and we compared the occurrence of dopamine supersensitivity psychosis episodes between the groups. There was no significant difference in any concentration of risperidone, 9-OH-risperidone, or active moiety between the groups although the with-CYP2D6*10 group had greater variabilities of these parameters compared to the without-CYP2D6*10 group. There was a lower rate of dopamine supersensitivity psychosis episodes in the without-CYP2D6*10 group (4/15, 26.7%) compared to the with-CYP2D6*10 group (11/21, 52.4%), but the difference was not significant. Although our findings were negative, largely because of the small sample size, these results suggest that (1) patients with an impaired functional allele of CYP2D6 may have higher concentrations of risperidone and its active metabolite and that (2) these patients may experience more frequent dopamine supersensitivity psychosis episodes.

Physiologically Based Modeling Approach to Predict Dopamine D2 Receptor Occupancy of Antipsychotics in Brain: Translation From Rat to Human.

Receptor occupancy (RO) is a translational biomarker for assessing drug efficacy and safety. We aimed to apply a physiologically based pharmacokinetic (PBPK) modeling approach to predict the brain dopamine D2 RO time profiles of antipsychotics. Clozapine and risperidone were modeled together with their active metabolites, norclozapine and paliperidone, First, in PK-Sim a rat PBPK model was developed and optimized using literature plasma PK data. Then, blood-brain barrier parameters including the expression and efflux transport kinetics of P-glycoprotein were optimized using literature microdialysis data on brain extracellular fluid (brainECF), which were further adapted when translating the rat PBPK model into the human PBPK model. Based on the simulated drug and metabolite concentrations in brainECF, drug-D2 receptor binding kinetics (association and dissociation rates) were incorporated in MoBi to predict RO. From an extensive literature search, 32 plasma PK data sets (16 from rat and 16 from human studies) and 23 striatum RO data sets (13 from rat and 10 from human studies) were prepared and compared with the model predictions. The rat PBPK-RO model adequately predicted the plasma concentrations of the parent drugs and metabolites and the RO levels. The human PBPK-RO model also captured the plasma PK and RO levels despite the large interindividual and interstudy variability, although it tended to underestimate the plasma concentrations and RO measured at late time points after risperidone dosing. The developed human PBPK-RO model was successfully applied to predict the plasma PK and RO changes observed after risperidone dose reduction in a clinical trial in schizophrenic patients.

Rats and rabbits as pharmacokinetic screening tools for long acting intramuscular depots: case study with paliperidone palmitate suspension.

Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (Tmax) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0-28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8-10 days). Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).

Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2.

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

Prolactin levels: sex differences in the effects of risperidone, 9-hydroxyrisperidone levels, CYP2D6 and ABCB1 variants.

AIM: The role of sex on the association of plasma prolactin levels with risperidone (R) and 9-hydroxyrisperidone (9-OHR) concentrations is investigated. METHODS: Plasma R and prolactin concentrations, CYP2D6 and exon 21 and 26 ABCB1 gene variants were studied in 110 patients. RESULTS: In females, a 1 ng/ml increase in R levels was associated with a significant 1.02% increase in prolactin levels. In males, a 1 ng/ml increase in 9-OHR levels was associated with a significant 1.18% increase in prolactin levels. ABCB1 haplotype 12 had significant but opposite effects in males and females. In the combined sample, 9-OHR, but not R levels had significant effects on prolactin levels. CONCLUSION: Genes had sex-specific effects on risperidone-associated prolactin elevations.

Quantitative determination of risperidone, paliperidone and olanzapine in human serum by liquid chromatography-tandem mass spectrometry coupled with on-line solid-phase extraction.

A recent guideline recommends therapeutic drug monitoring for risperidone, paliperidone and olanzapine, which are frequently used second-generation antipsychotics. We developed a simple high-performance liquid chromatography-tandem mass spectrometry coupled with an online solid-phase extraction method that can be used to measure risperidone, paliperidone and olanzapine using small (40 µL) samples. The analytes were extracted from serum samples automatically pre-concentrated and purified by C8 (5 µm, 2.1 × 30 mm) solid-phase extraction cartridges, then chromatographed on an Xbidge™ C18 column (3.5 µm, 100 × 2.1 mm) thermostatted at 30°C with a mobile phase consisting of 70% acetonitrile and 30% ammonium hydroxide 1% solution at an isocratic flow rate of 0.3 mL/min, and detected with tandem mass spectrometry. The assay was validated in the concentration range from 2.5 to 160 ng/mL. Intra- and inter-day precision for all analytes was between 1.1 and 8.2%; method accuracy was between 6.6 and 7.6%. The risperidone and paliperidone assay was compared with a high-performance liquid chromatography-ultraviolet assay currently used in our hospital for risperidone and paliperidone therapeutic drug monitoring, and the results of weighted Deming regression analysis showed good agreement. For the olanzapine assay, we compared 20 samples in separate re-assays on different days; all the relative errors were within the 20% recommended limit.

Genotyping as a Key Element of Sample Size Optimization in Bioequivalence of Risperidone Tablets.

BACKGROUND AND OBJECTIVES: Risperidone is a derivative of benzisoxazole and is widely used for schizophrenia and other psychiatric illnesses in both adults and children. Previous studies have confirmed that it is a highly variable drug (within-subject variability ≥ 30%). To reduce the large sample size required for bioequivalence researches on highly variable drugs, a role for genotyping in the design of the bioequivalence study was employed. METHODS: A randomized, open-label, two-period crossover study was adopted: 20 subjects with specific genotypes carrying cytochrome P450 (CYP) 2D6*10 were randomized to two groups to receive a single oral dose of trial formulation or reference formulation with a 2-week washout period. Blood concentrations of risperidone (parent drug) and 9-hydroxy risperidone (active metabolite) were measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Eighteen out of the 20 subjects completed the study (two did not finish the test in the second period). The pharmacokinetic parameters of AUClast, AUC∞ and Cmax for the 18 subjects after a single oral dose of the trial or reference preparation were 216.1 ± 88.7 and 220.5 ± 96.8 ng·h/mL; 221.6 ± 93.1 and 226.4 ± 103.5 ng·h/mL; 36.7 ± 10.3 and 36.0 ± 10.2 ng/mL, respectively. The CVw of risperidone in natural logarithm-transformed Cmax was 22.4 and 25.38% for 9-hydroxy risperidone. CONCLUSIONS: The test formulation met the Food and Drug Administration guidelines and regulation criteria for bioequivalence. By controlling the genotype, it could actually help reduce the CVw, which may be a feasible method to decrease the sample size for the bioequivalence study of highly variable drugs.

Serum Concentrations of Paliperidone After Administration of the Long-Acting Injectable Formulation.

BACKGROUND: The pharmacokinetics of long-acting intramuscular paliperidone in a naturalistic setting is not well documented. The objective of this study was to investigate the relationship between dose and serum concentrations of paliperidone using data from a routine therapeutic drug monitoring service. METHODS: Serum concentration measurements in 310 samples from 110 male and 75 female patients receiving depot injections of paliperidone were retrospectively retrieved from the therapeutic drug monitoring database. RESULTS: The median dose was 100 mg every 28 days. The median concentration/dose (C/D) ratio of paliperidone was 16.1 (nmol/L)/(mg/d), with a 10-90 percentile range of 7.8-31.0 (nmol/L)/(mg/d). Dose-adjusted serum concentrations were 33% higher in patients 65 years or older and more than 50% lower in patients taking the p-glycoprotein inducer carbamazepine. There were no significant effects of sex or dose on the C/D ratio. The median serum concentrations of paliperidone at the end of the dose interval were 31 nmol/L at an intramuscular dose of 50 mg/28 d, 53 nmol/L after a dose of 75 mg/28 d, 59 nmol/L after a dose of 100 mg/28 d, and 93 nmol/L after a dose of 150 mg/28 d. Forty-five percent of the measurements were lower than the suggested therapeutic range of 20-60 ng/mL (47-140 nmol/L). CONCLUSIONS: The data show a 4-fold interindividual difference in dose-adjusted serum concentrations within the 10-90 percentile range and illustrate the significant effects of age and p-glycoprotein induction on the pharmacokinetics of paliperidone. The study also indicates that at least in some patients, it might take longer time than anticipated to reach steady state.

Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication.

Paliperidone prolongs cardiac repolarization in a concentration-dependent manner. Meanwhile, continuous infusion of intravenous lipid emulsion (ILE) has been established as a detoxification therapy for lipophilic drugs. However, this change in pharmacokinetics of various drugs following ILE administration remains to be clarified. Our objective is to clarify the effect of continuous infusion of ILE on the pharmacokinetics of overdosed paliperidone in rats. Paliperidone (20mg/kg) was administered orally to free-moving male Wistar rats. Continuous infusion (initial loading dose: 4ml/kg for 10min, followed by 4ml/kg/h for 12h) of ILE or acetated Ringer's solution (AR) was initiated 30min after paliperidone administration. Plasma concentration profile of paliperidone was monitored for 12h after administration. The plasma concentration and tissue/plasma concentration ratios of paliperidone were compared between ILE and AR groups. The rat group infused with ILE showed a higher area under the concentration-time curve (mean [S.D.]: 6102 [900.9] vs. 3407 [992.1]nghml-1, p=0.02) and longer elimination half-time (t1/2) (4.1 [0.9] vs. 2.2 [0.4]h, p=0.02) compared with the AR group. Tissue/plasma concentration ratios of paliperidone were lower in ILE rats than in AR rats (1.98 [0.70] vs. 3.82 [1.47] in the heart, p=0.04; 0.28 [0.29] vs. 1.27 [0.58] in the brain, p<0.001). In conclusion, continuous infusion of ILE would reduce tissue distribution and prolonged the t1/2 of paliperidone in rats. These results suggest that continuous infusion of ILE has potential as an emergency treatment for acute paliperidone intoxication.