RESUMO
Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.
Assuntos
Clozapina/análogos & derivados , Modelos Biológicos , Esquizofrenia , Adulto , Idoso , Clozapina/administração & dosagem , Clozapina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , UruguaiRESUMO
In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from 4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to 101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h, respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients regarding both the rate and extent of absorption.
Assuntos
Antipsicóticos/farmacocinética , Clozapina/farmacocinética , Esquizofrenia/tratamento farmacológico , Administração Oral , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Estudos Cross-Over , Humanos , Espectrometria de Massas em TandemRESUMO
The aim of the present study was to determine the prescribing practice for clozapine (CAS 5786-21-0) as well as the plasma levels of clozapine and its main metabolite norclozapine (CAS 6104-71-8) in Mexican patients. A prospective study was performed in 69 in and out psychotic patients taking clozapine. Blood samples were taken at steady state. Plasma concentrations of clozapine and norclozapine were determined by HPLC. The results showed that the mean daily dose administered was 250 mg/d. Plasma levels showed a large interindividual variability. Mean plasma levels were 411.3 +/- 328.12 ng/mL, for clozapine and 172.0 +/- 129.9 ng/mL for norclozapine. When data were compared with those reported in other populations, it was found that although the dose was lower than that reported in Caucasians, the plasma levels were similar. As a result, the predictive models for the estimation of clozapine concentration in Caucasians were not appropriate for application in Mexican patients. The findings suggest ethnic differences in the ratio dose/plasma levels of clozapine in Mexican patients. Further studies are required to expand the observations.
Assuntos
Antipsicóticos/sangue , Clozapina/análogos & derivados , Esquizofrenia/sangue , Adulto , Idoso , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Cromatografia Líquida de Alta Pressão , Clozapina/efeitos adversos , Clozapina/sangue , Clozapina/farmacocinética , Monitoramento de Medicamentos , Etnicidade , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Se presenta el caso de un varón de 37 años, esquizofrénico en tratamiento con Clozapina. Es hospitalizado por neurotropenia severa y brusca, evolucionando rápidamente con compromiso de conciencia, agitación psicomotora, temperatura alta e hipotensión refractaria a aporte de volumen. Manejado en la Unidad de Cuidados Intensivos, se asiste a complicaciones renales y respiratorias, destacando la gran hipertonía muscular generalizada. Finalmente, el paciente fallece por paro cardio-respiratorio en asistolía. Se analiza el cuadro de hipertermia y se le relaciona con el uso de neurolépticos, describiéndose la toxicidad por clozapina, que produce neutropenia. Se plantea el diagnóstico diferencial entre el síndrome neuroléptico maligno, la hipertermia maligna y el síndrome serotoninérgico. Por último, se describe el manejo médico de la hipertermia.
Assuntos
Adulto , Masculino , Humanos , Clozapina/efeitos adversos , Síndrome Maligna Neuroléptica/etiologia , Doença Aguda , Antipsicóticos/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Clozapina/farmacocinética , Diagnóstico Diferencial , Hipertermia Maligna/terapia , Neutropenia/etiologia , Síndrome da Serotonina/etiologiaAssuntos
Humanos , Masculino , Feminino , Clozapina/efeitos adversos , Clozapina/farmacocinética , Clozapina/farmacologia , Clozapina/diagnóstico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Antipsicóticos/metabolismo , Antipsicóticos/toxicidade , Antipsicóticos/diagnóstico , Esquizofrenia , Depressão , Doença de Parkinson , Diabetes Mellitus , Anorexia NervosaRESUMO
Objetivo: Revisar las características del antipsicótico atípico olanzapina y analizar los estudios de eficacia clínica disponibles hasta ahora. Método: Se seleccionaron los trabajos más relevantes, los que fueron analizados desde el punto de vista de la eficacia clínica y de la seguridad del fármaco. Resultados: La olanzapina demostró eficacia sobre los síntomas positivos, negativos y depresivos de la esquizofrenia, mejorando la calidad de vida y disminuyendo las rehospitalízaciones. Tuvo escasos efectos colaterales y se asoció significativamente menos con la aparición de síntomas extrapiramidales y disquinesía tardía en comparación con el haloperidol. Conclusiones: La olanzapina parece representar una alternativa eficaz y segura para el tratamiento de la sintomatología esquizofrénica
Assuntos
Humanos , Antipsicóticos/farmacocinética , Esquizofrenia/tratamento farmacológico , Clozapina/farmacocinética , Haloperidol/farmacocinética , Risperidona/farmacocinética , Transtornos Psicóticos/tratamento farmacológicoRESUMO
Derivado dibenzodiazepìnico, a clozapina é considerada um neuroléptico atìpico por näo desencadear habitualmente reaçöes extrapirâmidais (REP). Sua atividade terapêutica representa um grande progresso no tratamento da esquizofrenia, tendo sido demonstrado que, em doentes refratários e graves, é mais eficaz que a clorpromazina, agindo tanto nos sintomas positivos quanto nos negativos. Além da virtual ausência de REP, näo se observaram, nestes 20 anos, casos confirmados de discinesia tardia com seu uso. Outra caracterìstica que a diferencia dos neuroléticos usuais é a de näo aumentar os nìveis plasmáticos de prolactina. Apesar de seu potencial terapêutico promissor, a incidência relativamente elevada de agranulocitose em 1 a 2//dos casos impöe restriçäo de seu emprego de forma mais ampla na prática psiquiátrica