Assuntos
Rotulagem de Medicamentos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Disponibilidade Biológica , Cálculos da Dosagem de Medicamento , Interações Medicamentosas , Rotulagem de Medicamentos/métodos , Rotulagem de Medicamentos/normas , Humanos , Preparações Farmacêuticas/administração & dosagemRESUMO
The criterion for assessing whether a drug prolongs QT as described in the International Conference on Harmonization topic E14 guideline does not explicitly account for individual drug concentrations. The authors' experience with reviewing QT studies indicates that understanding the relationship, if any, between individual drug concentration and QT change provides important additional information to support regulatory decision making. Therefore, regulatory reviews of "thorough QT" studies routinely include a characterization of the concentration-QT relationship. The authors provide examples to illustrate how the concentration-QT relationship has been used to plan and interpret the thorough QT study, to evaluate QT risk for drugs that have no thorough QT studies, to assess QT risk in subpopulations, to make dose adjustments, and to write informative drug labels.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Drogas em Investigação/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Arritmias Cardíacas/diagnóstico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Guias como Assunto , Humanos , Síndrome do QT Longo/diagnóstico , Medição de Risco/métodos , Fatores de RiscoRESUMO
Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.
Assuntos
Aprovação de Drogas/legislação & jurisprudência , Rotulagem de Medicamentos/legislação & jurisprudência , Farmacocinética , Farmacologia Clínica , Benzazepinas/administração & dosagem , Benzazepinas/efeitos adversos , Benzazepinas/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Ciclosporinas/administração & dosagem , Ciclosporinas/efeitos adversos , Ciclosporinas/uso terapêutico , Coleta de Dados , Técnicas de Apoio para a Decisão , Progressão da Doença , Esquema de Medicação , Avaliação de Medicamentos/métodos , Equinocandinas , Everolimo , Humanos , Aplicação de Novas Drogas em Teste/legislação & jurisprudência , Aplicação de Novas Drogas em Teste/estatística & dados numéricos , Lipopeptídeos , Lipoproteínas/administração & dosagem , Lipoproteínas/efeitos adversos , Lipoproteínas/uso terapêutico , Micafungina , Revisão por Pares , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/uso terapêutico , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Medição de Risco/métodos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência , United States Food and Drug Administration/normas , VareniclinaRESUMO
The potential sites for metabolism of centpropazine (CPZ) (an antidepressant) were evaluated in male Sprague-Dawley rats. The isolation and identification of the major metabolites formed in the presence of rat liver S9 fraction, intestine, and red blood cells under aerobic conditions were performed using high-performance liquid chromatography and electrospray ionization mass spectrometry. CPZ was found to be extensively metabolized to seven possible metabolites by liver S9 fraction in the presence of a nicotinamide adenine dinucleotide phosphate generating system at 37 degrees C. Both intestinal wall and red blood cells were also found to metabolize the compound. This metabolite structure was confirmed by comparison with that of its synthetic standard. The drug was stable in intestinal contents. On the basis of our finding, we propose the in vitro metabolic pathways for CPZ.
