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Determination of Plasma Concentration Reference Ranges for Risperidone and Paliperidone.

ABSTRACT: 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.

SUBMITTER: Korell J

PROVIDER: S-EPMC5613178 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Determination of Plasma Concentration Reference Ranges for Risperidone and Paliperidone.

Korell J J Green B B Remmerie B B Vermeulen A A

CPT: pharmacometrics & systems pharmacology 20170829 9

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 paliper ...[more]

PMID: 28614899

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Project description:BackgroundThis study aimed to investigate the influence of CYP2D6 polymorphisms on risperidone plasma concentrations in patients with schizophrenia. Based on pharmacogenomics, we examined whether plasma concentration of risperidone is associated with clinical response and adverse side-effects.MethodsWe recruited patients with chronic schizophrenia who were then treated with risperidone. The CYP2D6 genotypes were determined using targeted sequencing. All high-frequency mutation sites of the nine exons of the gene were assayed in the present study. Plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-RIS) were measured using high-performance liquid chromatography (HPLC). Psychiatric symptoms were monitored using The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Adverse effects were evaluated using the Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS). Follow-up visits were scheduled at weeks 2,4, and 8 after treatment initiation.ResultsAmong the 76 patients, 100 C > T (rs1065852), 1038 C > T (rs1081003), 1662 G > C (rs1058164), 2851 C > T (rs16947), and 4181G > C (rs1135840) variants were detected. The most common allele was CYP2D6*10 (81.6%), whereas CYP2D6*2 (9.2%) and CYP2D6*5 (17.1%) were relatively rare. Plasma levels of risperidone and the risperidone/9-OH risperidone ratio (R/9-OH) were significantly increased in individuals with CYP2D6*10 (P < 0.05). The change in PANSS score, weight, high-density lipoprotein (HDL) level, prolactin (PRL) level, and ESRS were significantly different from baseline, between the different genotypes (P < 0.01). Moreover, individuals with CYP2D6*10 homozygous (TT) mutations were associated with higher risperidone concentration and R/9-OH ratio than those with heterozygous mutations (CT) (P < 0.01). A change from baseline in BPRS scores was observed only during week 8 and was different between heterozygous and homozygous mutations. As for the C2851T polymorphism, the incidence of adverse metabolic effects was significantly different between the C/C and C/T genotypes (P < 0.01). Regarding the G4181C polymorphisms, the changes from baseline in GLU and TG, were different between the C/C and C/G genotypes (P < 0.01).ConclusionsThe genotype of CYP2D6 significantly influences the plasma concentration of risperidone and may subsequently influence the adverse side-effects following risperidone treatment, while also exerting a slight influence on clinical outcomes.

Project description:PURPOSE:Reducing the dosing frequency of antipsychotics (APs) with long-acting injectables (LAIs) such as once-monthly paliperidone palmitate (PP1M) can improve adherence and clinical outcomes for schizophrenia patients. This US study compared physical and psychiatric comorbidity-related outcomes, AP adherence, healthcare resource utilization (HRU), and costs pre- and post-transition to PP1M among schizophrenia patients treated with oral risperidone/paliperidone pre-PP1M transition. METHODS:Health insurance claims from the IQVIA™ PharMetrics Plus database (01/01/2012-07/31/2018) were used to identify adults with???2 schizophrenia diagnoses,???1 claim for PP1M, and???30 days of treatment with oral risperidone/paliperidone in the 60 days before the first PP1M claim (i.e., the index date). Comorbidity-related outcomes, adherence to APs (measured via the proportion of days covered [PDC]), all-cause per-patient-per-month (PPPM) HRU, and all-cause PPPM medical, pharmacy, and total costs (i.e., sum of medical and pharmacy costs) during the 6-month periods pre- and post-transition to PP1M were compared using generalized estimating equation models adjusted for repeated measurements. Analyses were replicated in the subset of patients with???1 all-cause inpatient stay pre-PP1M transition. FINDINGS:Among 427 schizophrenia patients transitioning from oral risperidone/paliperidone to PP1M, the mean age was 41.1 years and 37.9% were female. Following the PP1M transition, patients were less likely to have claims with a diagnosis for psychoses (odds ratio [OR] 0.41; P?<?0.001), hypertension (OR 0.80; P?=?0.011), depression (OR 0.70; P?<?0.001), drug abuse (OR 0.60; P?<?0.001), substance-related and addictive disorders (OR 0.73; P?=?0.003), bipolar and related disorders (OR 0.59; P?<?0.001), sleep-wake disorders (OR 0.68; P?=?0.017), anxiety disorders (OR 0.78; P?=?0.034), and other conditions that may require a focus of clinical attention (OR 0.58; P?<?0.001). Mean PDC by APs was higher post-PP1M (mean?=?0.81) versus pre-PP1M (mean?=?0.68) transition. Post-PP1M, patients were less likely to have an all-cause emergency room visit (OR 0.51; P?<?0.001) or inpatient stay (OR 0.39; P?<?0.001) compared to pre-PP1M. All-cause total healthcare costs remained similar post- versus pre-transition to PP1M (mean monthly cost difference [MMCD]?=?$228; P?=?0.260). Pharmacy costs increased post-PP1M (MMCD?=?$960; P?<?0.001), but were offset by decreasing medical costs (MMCD?=?- $732; P?<?0.001), largely driven by lower costs related to inpatient stays (MMCD?=?- $695; P?<?0.001) and emergency room visits (MMCD?=?- $63; P?<?0.001). For patients with???1 all-cause inpatient stay pre-PP1M transition (N?=?177), a more pronounced improvement in comorbidity-related outcomes, a more pronounced reduction in HRU, and a reduction in total healthcare costs (MMCD?=?- $1308; P?<?0.001) were observed post-transition to PP1M. IMPLICATIONS:Among schizophrenia patients in the US, transitioning to PP1M following oral risperidone/paliperidone treatment was associated with improved comorbidity-related outcomes, higher adherence, and a reduction in HRU, while remaining cost neutral. Furthermore, patients with???1 all-cause inpatient stay pre-PP1M transition had significantly lower total healthcare costs post-PP1M transition.

Project description:BACKGROUND:This post hoc subgroup analysis of a randomized, double-blind trial evaluated the response to treatment with two long-acting injectable atypical antipsychotics, ie, paliperidone palmitate and risperidone long-acting injectable (RLAI), in subjects with schizophrenia experiencing clinically significant symptoms despite recent treatment with oral risperidone only or other oral antipsychotics. METHODS:Adult subjects were eligible for the 13-week, double-blind, double-dummy trial (NCT00589914) if they had an established diagnosis of schizophrenia for at least one year and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 inclusive at screening. Subjects received either paliperidone palmitate (234 mg, day 1; 156 mg, day 8; then once-monthly flexible dosing) or RLAI (25-50 mg biweekly, with oral risperidone supplementation on days 1-28), plus matched placebo injections/tablets. RESULTS:This post hoc analysis reports data on 747 subjects who, within 2 weeks of starting double-blind study medication, had reportedly received oral risperidone only (paliperidone palmitate group, n = 126; RLAI group, n = 107), other oral antipsychotics (paliperidone palmitate group, n = 199; RLAI group, n = 203), or no antipsychotic (paliperidone palmitate group, n = 56; RLAI group, n = 56). Mean PANSS total scores improved significantly at end point across all subgroups (mean change from baseline ranged from -17.5 to -19.5, all P < 0.0001). Clinical Global Impression-Severity and Personal and Social Performance scale measures also significantly improved from baseline (all P < 0.0001). CONCLUSION:Treatment with paliperidone palmitate or RLAI resulted in a significant reduction in the symptoms of schizophrenia irrespective of previous recent treatment with oral risperidone only or other oral antipsychotics. For subjects who had previously received oral risperidone only, the difference in formulation was the main change in the intervention because the molecule delivered remained the same or similar. These data support the contribution of a long-acting formulation to improving the treatment response and suggest that nonadherence may be a significant contributor to inadequate efficacy of oral formulations in subjects with schizophrenia.

Project description:OBJECTIVE:First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone. DESIGN:Double-blind, randomized study. SETTING:Outpatient or inpatient. PARTICIPANTS:Adults with established (?1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l-6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days. MEASUREMENTS:Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ?30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted. RESULTS:Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period. CONCLUSION:During the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.

Project description:BackgroundA considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic studies often rely on the merging of venous and capillary sampling. Drug levels in capillary plasma may be different from those in venous plasma, Thus, correlation between capillary and venous drug levels needs to be established.MethodsLiquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to develop the method. Piperaquine was measured in 205 pairs of capillary and venous plasma samples collected simultaneously at ≥24hr post dose in children, pregnant women and non-pregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Standard three-dose regimen over three days applied to all participants with three 40mg dihydroartemisinin/320mg PQ tablets per dose for adults and weight-based dose for children. Correlation analysis was performed using the program Stata® SE12.1. Linear regression models were built using concentrations or logarithm transformed concentrations and the final models were selected based on maximal coefficient of determination (R2) and visual check.ResultsAn LC-MS/MS method was developed and validated, utilizing methanol as a protein precipitation agent, a Gemini C18 column (50x2.0mm, 5μm) eluted with basic mobile phase solvents (ammonium hydroxide as the additive), and ESI+ as the ion source. This method had a calibration range of 10-1000 ng/mL and carryover was negligible. Correlation analysis revealed a linear relationship: Ccap = 1.04×Cven+4.20 (R2 = 0.832) without transformation of data, and lnCcap = 1.01×lnCven+0.0125, (R2 = 0.945) with natural logarithm transformation. The mean ratio (±SD) of Ccap/Cven was 1.13±0.42, and median (IQR) was 1.08 (0.917, 1.33).ConclusionsCapillary and venous plasma PQ measures are nearly identical overall, but not readily exchangeable due to large variation. Further correlation study accounting for disposition phases may be necessary.

Dataset Information

Determination of Plasma Concentration Reference Ranges for Risperidone and Paliperidone.

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Determination of Plasma Concentration Reference Ranges for Risperidone and Paliperidone.

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