Amisulpride steady-state plasma concentration and adverse reactions in patients with schizophrenia: a study based on therapeutic drug monitoring data.

The aim of the study was to evaluate the reference range of amisulpride for Chinese patients with schizophrenia and to assess its possible influencing factors based on therapeutic drug monitoring information. The relative adverse reactions of patients induced by amisulpride were also systematically investigated. A total of 425 patients with schizophrenia were assessed, including Positive and Negative Syndrome Scales, Treatment Emergent Symptom Scale, blood routine examination, hepatorenal function, lipids, hormones, as well as myocardial enzymes at baseline, and following treatment with amisulpride for 8 weeks. The steady-state plasma concentration of amisulpride was assayed using two-dimensional liquid chromatography. At the same dose, the amisulpride plasma concentration of patients combined with clozapine was higher than that without clozapine. The therapeutic reference range of amisulpride can be defined as 230.3-527.1 ng/ml for Chinese patients with schizophrenia. The potential side effects appear to be associated with significantly increased levels of LDH, CK, creatine kinase isoenzyme (CK-MB), TC and decreased level of E 2 , relative to the amisulpride plasma concentration. These findings could provide individualized medication and reduce the adverse effects of amisulpride for Chinese patients with schizophrenia.

Modeling and Simulation for Individualized Therapy of Amisulpride in Chinese Patients with Schizophrenia: Focus on Interindividual Variability, Therapeutic Reference Range and the Laboratory Alert Level.

PURPOSE: To explain the high inter-individual variability (IIV) and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride, a population pharmacokinetic (PPK) model in Chinese patients with schizophrenia was built based on therapeutic drug monitoring (TDM) data to guide individualized therapy. PATIENTS AND METHODS: Plasma concentration data (330 measurements from 121 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCE I). The concentrations of amisulpride were detected by HPLC-MS/MS. Age, weight, sex, combination medication history and renal function status were evaluated as main covariates. The model was internally validated using goodness-of-fit, bootstrap and normalized prediction distribution error (NPDE). Recommended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model. RESULTS: A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentration in Chinese patients with schizophrenia. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. Age significantly affected the clearance of amisulpride and the final model was as follows: CL/F=1.04×(AGE/32)-0.624 (L/h). To avoid exceeding the laboratory alert level (640 ng/mL), the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg/d for patients aged 60 years, 800 mg/d for those aged 40 years and 1200 mg/d for those aged 20 years, respectively. CONCLUSION: Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions. The model can be used as a suitable tool for designing individualized therapy for Chinese patients with schizophrenia.

A novel and sensitive method for determination of amisulpride in human plasma by two-dimensional liquid chromatography.

A novel and sensitive heart-cutting two-dimensional liquid chromatography with ultraviolet detection method (2D-LC-UV) was developed and validated for determination of amisulpride in human plasma. The 2D-LC system consists of a first dimensional (1 D) LC column and a middle transfer column as well as a second-dimensional (2 D) LC column. After simple protein precipitation, the sample was directly injected into the introduction valve of the 2D-LC system. The 1 D column, playing a role of primary separation and preconcentration for complex plasma matrices, transferred the targets to the intermediate column. Following capture of targets on the middle column online, the analytes were transferred to the 2 D separation column by a six-port valve. The 2 D column, avoiding interference from the plasma matrix, completed further separation and quantification. An assistant pump was optimized for primary enrichment as well as final elution in the heart-cutting mode. The analytical time of amisulpride was 7.401 min. The accuracy was between 0.48 and 8.49%, while the intra- and inter-day precisions ranged from 0.9 to 3.1% and from 1.7% to 3.3%, respectively. The linear range of amisulpride was 48.15-2,407.59 ng/ml, while the extraction recovery was 98.7-101.3%. The strategy established in the study, which was successfully applied to therapeutic drug monitoring of amisulpride for routine clinical detection, displays high sensitivity, good repeatability, convenience and low cost.

Amisulpride: Real-World Evidence of Dose Adaptation and Effect on Prolactin Concentrations and Body Weight Gain by Pharmacokinetic/Pharmacodynamic Analyses.

BACKGROUND: Amisulpride is an antipsychotic used in a wide range of doses. One of the major adverse events of amisulpride is hyperprolactinemia, and the drug might also induce body weight gain. OBJECTIVE: The aims of this work were to characterize the pharmacokinetics of amisulpride in order to suggest optimal dosage regimens to achieve the reference range of trough concentrations at steady-state (Cmin,ss) and to describe the relationship between drug pharmacokinetics and prolactin and body weight data. METHODS: The influence of clinical and genetic characteristics on amisulpride pharmacokinetics was quantified using a population approach. The final model was used to simulate Cmin,ss under several dosage regimens, and was combined with a direct Emax model to describe the prolactin data. The effect of model-based average amisulpride concentrations over 24 h (Cav) on weight was estimated using a linear model. RESULTS: A one-compartment model with first-order absorption and elimination best fitted the 513 concentrations provided by 242 patients. Amisulpride clearance significantly decreased with age and increased with lean body weight (LBW). Cmin,ss was higher than the reference range in 65% of the patients aged 60 years receiving 400 mg twice daily, and in 82% of the patients aged > 75 years with a LBW of 30 kg receiving 200 mg twice daily. The pharmacokinetic/pharmacodynamic model included 101 prolactin measurements from 68 patients. The Emax parameter was 53% lower in males compared with females. Model-predicted prolactin levels were above the normal values for Cmin,ss within the reference range. Weight gain did not depend on Cav. CONCLUSIONS: Amisulpride treatment might be optimized when considering age and body weight. Hyperprolactinemia and weight gain do not depend on amisulpride concentrations. Modification of the amisulpride dosage regimen is not appropriate to reduce prolactin concentrations and alternative treatment should be considered.

A new sensitive approach for spectrofluorimetric assay of Milnacipran and Amisulpride in real plasma and pharmaceutical preparations via complexation with Eosin Y dye.

An accurate, economic, rapid, reliable spectrofluorimetric assay was developing for the assay of definite anti-depressant drugs namely Amisulpride and Milnacipran hydrochloride, in those pharmaceutical preparation and biological fluid. The suggested method was established on the detection of quenching process resulting from the action of AMS and MCN to the native fluorescent EosinY. A binary complex between selected medications and Eosin Y was established in acetate buffer (0.2 M) at pH 3.3 & 4.0 for AMS and MCN respectively. The relative fluorescence capacity was determined at λex = 301.8 nm and λem = 542.7 nm. The calibration graphs had been linear through extent from 0.02 to 0.3 and 0.1-1 µg mL-1, to both dugs respectively. Detection limits have been 0.0047 & 0.0188 µg mL-1 while quantitation limits have been 0.0141 & 0.0569 µg mL-1 to AMS & MCN respectively. Developed assay has been validated in agreement with ICH recommendations. Due to high sensitivity of the described assay, it allows the quantitation of anti-depressant drugs through biological fluid.

Enhanced Oral Absorption of Amisulpride Via a Nanostructured Lipid Carrier-Based Capsules: Development, Optimization Applying the Desirability Function Approach and In Vivo Pharmacokinetic Study.

Amisulpride (AMS), a second generation antipsychotic, suffers from low oral bioavailability (48%). This might be due to its pH-dependent solubility or being a substrate of P-glycoprotein efflux pump. Nanostructured lipid carriers (NLCs) were proposed in this study to enhance the oral absorption of AMS. AMS-NLCs were prepared by solvent evaporation technique according to (21.41.31) factorial design, whereas the type of solid lipid (tripalmitin or Gelucire® 43/1), lipid to drug ratio (7:1, 10:1, or 13:1) and type of external suspending medium (double distilled water, 0.5% TSP pH 12, 1% HPMC or 2.5% glycerin) were the independent variables. The average entrapment efficiency, particle size, polydispersity index, and zeta potential of the prepared formulations ranged from 29.01 to 69.06%, 184.9 to 708.75 nm, 0.21 to 0.59, and - 21 to - 33.55 mV, respectively. AMS-NLCs were optimized according to the desirability function to maximize the entrapment efficiency and minimize the particle size. Formulae G12, G10, and G7 with the highest desirability values of 0.915, 0.84, and 0.768, respectively, were chosen for further investigations. Novel AMS-NLCs capsules were prepared from the lyophilized formulations (TG7 and MG10) to enhance stability and increase patient compliance. The capsules were evaluated in terms of weight variation, content uniformity, and in vitro release pattern. The pharmacokinetics of AMS-NLCs capsules (formula TG7) were tested in rabbits compared to the commercial Amipride® tablets. The relative bioavailability of AMS-NLCs capsules was found to be 252.78%. In conclusion, the NLC-based capsules show potential to improve the oral bioavailability of AMS.

Oral Bioavailability Enhancement of Amisulpride: Complexation and its Pharmacokinetics and Pharmacodynamics Evaluations.

BACKGROUND: Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness. OBJECTIVE: The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl ß- cyclodextrin (HPßCD). It has slow and erratic absorption after oral administration. METHODS: This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet. RESULTS: In-vitro study (100 % drug release in 15 minutes), and in-vivo study of an AL-type (linear type) phase solubility diagram indicated a complex of AMS-HP-ß-CD with the constant complex formation of 13245 M-1 at 37°C. The complex formation was confirmed by DSC, IR, and X-ray diffraction. The extent of absorption of the complex was determined in rats and was compared with that of pure drug and the market product. The peak plasma concentration of pure drug was 30.05 ± 1.3 ng/ml (Cmax) at 60 ± 3 min, whereas with the market product the value was 54.85 ± 1.2 ng/ml at 40 ± 1 min and with AMS-HPßCD inclusion complex the value was 79.01 ± 1.5 ng/ml. The AUCtot of the pure drug was 2980.34±3.6, the market product was 7238.73±2.9 and of the inclusion complex was 11871.1±2.8. CONCLUSION: Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%.

Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP).

OBJECTIVE: Antipsychotic drug sensitivity in very late-onset schizophrenia-like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). METHODS: Blood drug concentration, prolactin, symptoms and extrapyramidal side-effects (EPS) were serially assessed during dose titration. [18 F]fallypride imaging was used to quantify D2/3 receptor occupancy. Average steady-state amisulpride concentration (Caverage, ng/ml) was estimated by incorporating pharmacokinetic (PK) data into an existing population PK model (25 AD participants, 20 healthy older people). RESULTS: Eight patients (target 20) were recruited (six women; 76 + - 6 years; six treatment compliant; five serially sampled; three with paired imaging data). Mean + - SD symptom reduction was 74 ± 12% (50-100 mg/day; 92.5 + -39.4 ng/ml). Mild EPS emerged at 96 ng/ml (in AD, severe EPS, 50 mg/day, 60 ng/ml). In three participants, imaged during optimal treatment (50 mg/day; 41-70 ng/ml), caudate occupancy was 44-59% (58-74% in AD across a comparable Caverage). CONCLUSIONS: Despite the small sample size, our findings are highly relevant as they suggest that, as in AD, 50 mg/day amisulpride is associated with >40% occupancy and clinically relevant responses in VLOSLP. It was not possible to fully characterise concentration-occupancy relationships in VLOSLP, and it is thus unclear whether the greater susceptibility of those with AD to emergent EPS was accounted for by increased central drug access. Further investigation of age- and diagnosis-specific threshold sensitivities is warranted, to guide amisulpride prescribing in older people, and therapeutic drug monitoring studies offer a potentially informative future approach. Copyright © 2017 John Wiley & Sons, Ltd.

Causas y manejo de la hiperprolactinemia por antipsicóticos / Causes and management of antipsychotic-induced hyperprolactinemia

Los tratamientos farmacológicos de enfermedades psiquiátricas crónicas pueden inducir cambios en los niveles séricos de prolactina (PRL), como ocurre con los fármacos utilizados en el tratamiento del trastorno bipolar. Este efecto tiene consecuencias clínicamente relevantes para los pacientes, como disfunciones sexuales, osteoporosis o neoplasias sensibles a la PRL. La elevación de los niveles séricos de PRL es un efecto muy común del tratamiento con antipsicóticos, y hasta hace muy poco las diferencias entre los diversos compuestos de esta clase de fármacos no estaban valoradas. Los antipsicóticos típicos causan un incremento importante de los niveles séricos de PRL en comparación con los antipsicóticos atípicos (amisulprida, risperidona y paliperidona). La asenapina, la olanzapina y la ziprasidona tienen un efecto más ligero sobre los niveles de PRL. La lurasidona y la quetiapina no parecen inducir un incremento de la PRL, mientras que el aripiprazol, incluso en dosis altas, induce una disminución de la PRL. En el manejo clínico de la hiperprolactinemia inducida por antipsicóticos se puede valorar el cambio a un fármaco con perfil de impacto menor sobre la PRL, o el tratamiento integrado con un tratamiento que no afecte o disminuya los niveles séricos de PRL, por ejemplo con el litio, siempre teniendo en cuenta el equilibrio entre efectividad y tolerabilidad, y el perfil y las necesidades del paciente

Pharmacological treatments for chronic psychiatric illness can induce changes in prolactin (PRL) serum, including drugs that are used for the treatment of bipolar disorder. This effect has clinically relevant consequences for patients, such as sexual dysfunction, osteoporosis or tumors sensitive to PRL. An increase in PRL serum level is a common effect of treatment with antipsychotics, and until recently, the differences between various compounds of this class of drugs were not evaluated. Typical antipsychotics cause a significant increase in PRL serum compared with atypical antipsychotics (amisulpride, risperidone and paliperidone). Asenapine, olanzapine and ziprasidone have a slight effect on PRL levels. Lurasidone and quetiapine did not appear to cause an increase in PRL, whereas aripiprazole, even at high doses, causes PRL to decrease. In the clinical management of antipsychotic-induced hyperprolactinemia, one can assess the value of switching to a drug with less of an impact on PRL, or an integrated treatment with one that has no effect on or decreases PRL serum levels, for example with lithium, while taking into account the balance between effectiveness and tolerability and the patient's profile and needs