Clozapine levels and outcomes in Serbian patients with treatment-resistant psychotic disorders previously treated without measuring clozapine levels (CLOSER).

Clozapine remains the only pharmacological treatment option for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of clozapine is recommended, although evidence for the therapeutic range of 350-600 ng/ml is limited. In various countries including Serbia, TDM of clozapine is not routinely performed. This study evaluated the distribution of clozapine levels and their relationship with clinical outcomes in Serbian patients who had not undergone prior TDM. 140 Patients with treatment-resistant schizophrenia and schizo-affective disorder were enrolled. Clozapine levels were measured by dried blood spot (DBS) analysis. Side effects were evaluated by GASS-c, severity of symptoms and functional impairment with WHODAS, CGI-S and GAF. Of the patients, 51.2% had subtherapeutic levels, 24.8% were in the therapeutic window, and 24% had supratherapeutic levels. Clozapine levels showed no association with side effects and a weak positive association with symptom severity and functional impairment. No serious side effects were observed in patients with clozapine levels surpassing 1000 ng/ml (n = 8). Based on these findings, we propose that the upper limit of the therapeutic range should not be regarded as an absolute barrier, and guidelines should allow for a personalized approach when prescribing clozapine.

Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus-An aripiprazole case study.

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (Cmax) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for Cmax ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.

Metabolic profiling of lumateperone in vitro and in vivo by UPLC-Q Exactive Orbitrap HRMS, and its pharmacokinetic study in rat plasma by LC-MS/MS.

Lumateperone is a novel agent approved by FDA for treatment of schizophrenia in adults. To elucidate the species differences in the of biotransformation of lumateperone and its pharmacokinetic (PK) characteristics in rats, the metabolite identification of lumateperone was carried out in rat, dog and human liver microsomes, and rat plasma after oral administration using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry HRMS. Furtherly, the PK characteristics of lumateperone and its N-demethylated metabolite (M3) in rat plasma were investigated using a validated LC-MS/MS method following intravenous and oral administration. Fourteen phase I metabolites were found in liver microsomes and ten of them were observed in rat plasma. N-demethylation, carbonylation, dehydrogenation, and piperazine ring cleavage were main metabolic pathway of lumateperone. No unique metabolites were formed in human liver microsomes. After rapid absorption in rats, lumateperone was quickly metabolized and eliminated with bioavailability of less than 5%. The exposure level of M3 was about 1.5-fold higher than that of lumateperone in rat plasma. Lumatperone underwent extensive metabolism and was absorbed rapidly in rats. Metabolite M3 had equivalent or slightly higher exposure levels than lumateperone. This study provides essential PK information to facilitate further pharmacodynamic researches of lumateperone.

Microsampling Techniques Suitable for Therapeutic Drug Monitoring of Antipsychotics.

BACKGROUND: Therapeutic drug monitoring (TDM) of antipsychotics for dose titration or detection of noncompliance is not uncommon in daily practice. Normally, TDM implies measuring a drug concentration in venous blood samples. This technique is invasive and requires trained assistants and patients normally need to go to an outpatient clinic. Over the past decades, sensitivity of analytical equipment has improved leading to a growing interest in microsampling techniques. These techniques are minimally invasive, require a small volume (<100 µL), usually result in stable samples, and can be collected by the patient or a caregiver at home. Before a microsampling technique can be used in daily routine, proper method development and a clinical validation study should be performed. METHOD: For this review, the databases of PubMed and Embase were systematically searched. Currently available microsampling techniques for antipsychotics in blood, serum, or plasma are summarized. Subsequently, it has also been assessed whether these techniques are sufficiently validated for TDM monitoring in daily practice. RESULTS: Several microsampling techniques are available today, for example, dried blood spot sampling, dried plasma extraction cards, and volumetric absorptive microsampling. Eighteen studies were identified in which a microsampling technique for 1 or a few antipsychotics was chemically analytically and clinically validated. However, the majority of these studies have relevant shortcomings that mean its usefulness for different antipsychotics is not yet well established. CONCLUSIONS: Microsampling for TDM can be recommended for patients using clozapine. For TDM of other antipsychotics, it is a very promising development.

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

Variación intraindividual en los niveles plasmáticos de clozapina y norclozapina en la práctica clínica / Intra-individual variation of clozapine and norclozapine plasma levels in clinical practice

INTRODUCCIÓN: Los niveles plasmáticos de clozapina son útiles para monitorizar el cumplimento farmacológico, pero también para evaluar y prevenir los efectos secundarios. Recientemente, se ha propuesto realizar controles plasmáticos a todos los pacientes para prevenir recaídas. A pesar de ello, también se ha documentado una alta variabilidad intraindividual, aunque los estudios tienen algunas limitaciones. MÉTODOS: Aquí analizamos las diferencias entre 2determinaciones de niveles plasmáticos con al menos un año de diferencias en un subgrupo de 28 pacientes (82% hombres, media de edad=47,9 años) con diagnósticos de psicosis no afectiva y en remisión clínica con dosis de clozapina y niveles de tabaquismo estable. RESULTADOS: Encontramos un incremento no significativo de los niveles de clozapina (0,30mg/l [DE=0,14] vs. 0,32 [DE=0,17]; t=-0,858, p = 0,40) y un descenso significativo de la norclozapina (0,27 [DE=0,11] vs. 0,22 [DE=0,10]; t=3,27; p = 0,003]. Calculamos el coeficiente de variación absoluto (CV) entre la primera y segunda determinación. El CV del 20% en los niveles de clozapina y norclozapina se encontró en el 46 y el 57% de los casos, respectivamente, mientras que el CV 50% se obtuvo en el 20,7 y el 13,8%. Discutimos las causas potenciales de CV tan altos. CONCLUSIONES: Nuestro estudio encontró una alta variación intraindividual incluso en un subgrupo de pacientes especialmente estables, lo que sugiere que la monitorización rutinaria sería adecuada para detectar cambios significativos de los niveles. Creemos que los clínicos deberían ser cautos a la hora de asumir pobre cumplimiento terapéutico a la hora de explicar cambios de los niveles plasmáticos no acompañados de cambios clínicos

INTRODUCTION: Clozapine plasma levels are useful to monitor drug compliance, and also to assess and to prevent some side effects. Recently, routine monitoring to all clozapine-treated patients has been proposed to prevent relapses. However, high intra-individual variability in plasma levels has been reported too, although these studies have some limitations. METHODS: We analysed differences between 2clozapine plasma levels separated by at least one year in a subgroup of 28 outpatients (82% male, mean age 47.9 years-old) with diagnosis of non-affective psychosis in clinical remission whose clozapine doses and smoking habits remained unchanged. RESULTS: We found a non-significant increase in clozapine plasma levels [.30mg/L (SD=.14) vs. .32 (SD=.17); t=-.858, p=.40] and a significant decrease in norclozapine plasma levels [.27 (SD=.11) vs. .22 (SD=.10); t=3.27; p=.003]. Absolute coefficient of variation (CV) between first and second assessment were calculated. Forty-six and fifty-seven percent of cases had CV 20% in clozapine and norclozapine, respectively. CV of 50% was seen in 20.7% and 13.8% of clozapine and norclozapine test respectively. We discussed potential causes of such high CV. CONCLUSIONS: Our study suggest high intra-individual variation even in a subgroup of very stable patients, which suggest that routine monitoring of these levels may be indicated in order to detect significant plasma variations. We think that clinicians should act with caution in case of a sudden decrease in plasma level. In the absence of obvious symptom severity variation, sources of intra-individual fluctuations might be considered first, before assuming poor compliance

Investigation of possible association between Ser9Gly polymorphism of the D3 dopaminergic receptor gene and response to typical antipsychotics in patients with schizophrenia / Investigação da possível associação entre o polimorfismo Ser9Gly do gene do receptor de dopamina D3 e resposta a antipsicóticos típicos em pacientes com esquizofrenia

Typical antipsychotics have a high affinity for dopamine receptors. It is therefore of interest to investigate such loci in pharmacogenetic studies on psychosis. We investigated the hypothesis that Ser9Gly polymorphism of the DRD3 gene may play a role in the differences in individual response to typical antipsychotics between schizophrenic patients. The sample was composed of 53 good responders and 59 poor ones. No significant differences between the good and poor responders were found in the allelic distribution (good responders: Ser9 61.32 percent, Gly9 38.67 percent; poor responders: Ser9 64.40 percent, Gly9 35.59 percent; odds ratio, OR = 0.88, 0.49 < OR < 1.56; chi2 = 0.23, 1 degree of freedom, df, p = 0.63) and genotype distribution (good responders: Ser9/Ser9 37.73 percent, Ser9/Gly9 47.16 percent, Gly9/Gly9 15.09 percent; poor responders: Ser9/Ser9 42.37 percent, Ser9/Gly9 44.06 percent, Gly9/Gly9 13.55 percent; chi2 = 0.25, 2 df, p = 0.88). Nor was there any association with homozygosity (good responders: homozygous: 52.82 percent, heterozygous: 47.16 percent; poor responders: homozygous: 55.92 percent, heterozygous: 44.06 percent; odds ratio, OR = 0.88, 0.39 < OR < 1.99; chi2 = 0.11, 1 df, p = 0.74). The results did not support the hypothesis that Ser9Gly polymorphism of the DRD3 gene influences the response to typical antipsychotics in our sample of schizophrenics.

Antipsicóticos típicos apresentam alta afinidade pelos receptores dopaminérgicos, que são, portanto, regiões de interesse para os estudos de farmacogenética das psicoses. No presente estudo, investigamos a hipótese de que o polimorfismo Ser9Gly do gene do DRD3 possa exercer um papel na diferença de resposta inter-individual ao uso de antipsicóticos típicos em pacientes com esquizofrenia. Nossa amostra foi composta por 53 pacientes bons respondedores e 59 maus respondedores. Não houve diferenças nas distribuições alélicas (bons respondedores: Ser9 61,32 por cento, Gly9 38,67 por cento; maus respondedores: Ser9 64,40 por cento, Gly9 35,59 por cento; odds ratio, OR = 0,88, 0,49 < OR < 1,56; chi2 = 0,23, 1 degree of freedom, d.f., p = 0,63) e genotípica (bons respondedores: Ser9/Ser9 37,73 por cento, Ser9/Gly9 47,16 por cento, Gly9/Gly9 15,09 por cento; maus repondedores: Ser9/Ser9 42,37 por cento, Ser9/Gly9 44,06 por cento, Gly9/Gly9 13,55 por cento; chi2 = 0,25, 2 d.f., p = 0,88) entre os grupos. Não houve também associação com homozigosidade (bons respondedores: homozigotos: 52,82 por cento, heterozigotos: 47,16 por cento; maus repondedores: homozigotos: 55,92 por cento, heterozigotos: 44,06 por cento; odds ratio, OR = 0,88, 0,39 < OR < 1,99); chi2 = 0,11, 1 d.f., p = 0,74). Os resultados não dão suporte à hipótese de que o polimorfismo Ser9Gly do gene do DRD3 possa influenciar a resposta terapêutica aos antipsicóticos típicos na nossa amostra de pacientes com esquizofrenia.

Utilidad clínica de los niveles plasmáticos de neurolépticos en las psicosis / Clinical usefulness of the plasmatic levels of neuroleptics in the psychosis

La presente revisión bibliográfica tiene por objeto analizar fundamentos actuales de utilidad clínica de niveles plamáticos de neurolépticos en las psicosis. Se revisan los problemas metodológicos que explican diferencias de resultados de distintas investigaciones y, en especial, se analiza la existencia de una ventana terapéutica. Se concluye que al momento actual no existen suficientes evidencias que apoyan a esta última hipótesis, y se plantea la necesidad de ampliar las investigaciones aumentando el tamaño de las muestras

Determinación de niveles plasmáticos de neurolèpticos en psiquiatría / Determination of neuroleptic plasmatic levels in psychiatry

Se ofrece una revisión panorámica sobre la utilidad clìnica de las determinaciones de concentraciones plsmàticas de neurolèpticos en la práctica psiquiátrica, haciendo especial énfasis en los productos y pobremente definidos nivels plasmàticos terapéuticos de estas drogas, así como en las circunstancias generales bajo las cuales su determinación podría brindar un apoyo terapéutico adicional al psiquiatra. Se pone de manifiesto la necesidad de mayor profundidad en las investigaciones encaminadas a esclarecer las relaciones entre concentraciones y efectos de estos grupos de medicamentos

Determinación de niveles plasmáticos de neurolèpticos en psiquiatría / Determination of neuroleptic plasmatic levels in psychiatry

Se ofrece una revisión panorámica sobre la utilidad clìnica de las determinaciones de concentraciones plsmàticas de neurolèpticos en la práctica psiquiátrica, haciendo especial énfasis en los productos y pobremente definidos nivels plasmàticos terapéuticos de estas drogas, así como en las circunstancias generales bajo las cuales su determinación podría brindar un apoyo terapéutico adicional al psiquiatra. Se pone de manifiesto la necesidad de mayor profundidad en las investigaciones encaminadas a esclarecer las relaciones entre concentraciones y efectos de estos grupos de medicamentos

Niveles sanguíneos de los neurolépticos / Serum levels of neuroleptics

La determinación de los niveles sanguíneos de la drogas antipsicóticas podría, eventualmente, proporcionar: una guía para determinar las dosis terapéuticas óptimas y un margen de seguridad dentro de un rango de dosis, una manera de discriminar a los pacientes refractarios, la información farmacocinética necesaria para ajustar adecuadamente las dosificaciones, la posibilidad de predecir los efectos terapéuticos y una ayuda en la selección de la droga para cada caso en particular. Evidentemente, estos puntos son de una gran trascendencia para la clínica, lo que ha dado lugar a un creciente interés en la investigación de las relaciones entre los niveles sanguíneos de los neurolépticos y diversas respuestas: la antipsicótica, la extrapiramidal y la endócrina. En el presente documento se revisan, en primer término, las técnicas de laboratorio que se han utilizado con mayor frecuencia para la cuantificación de las concentraciones de los neurolépticos en las muestras biológicas: cromatografía, radio-inmunoanálisis y ensayo de radio-receptor. En segundo lugar se analiza la información disponible acerca de los antipsicóticos de uso más frecuente en nuestro medio, abordándose aspectos farmacocinéticos, estudios referentes a las relaciones entre los niveles sanguíneos de la droga y los tres tipos de respuestas mencionadas, así como la influencia de otras drogas en las concentraciones sanguíneas de los antipsicóticos. Finalmente, se comenta la información presentada y se señala su relevancia para la práctica clínica