Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Disfunção Cognitiva/diagnóstico , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Testes Neuropsicológicos , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Criança , Comportamento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/fisiologia , Ensaios Clínicos como Assunto , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Congressos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/psicologia , Humanos , Modelos Animais , Fatores de TempoRESUMO
This study was performed to identify an efficacious dosing regimen for U.S. Food and Drug Administration approval of topiramate for initial monotherapy in pediatric patients aged 2-9 years diagnosed with partial onset seizures and primary generalized tonic-clonic seizures using a pharmacometric bridging approach. The approval of topiramate in monotherapy of epilepsy for adult and pediatric patients (10-15 years) was based on efficacy and safety data from clinical trials. Our analysis showed that exposure-response relationship was similar between adult and pediatric patients (6-15 years) treated with topiramate as monotherapy for epilepsy. Specific dosing in pediatric patients 2-9 years of age was derived and included in the simulations by matching predicted exposures in pediatric patients (2-9 years) to a range of exposures observed in adult and pediatric patients (6-9 years) in a previously conducted clinical trial. The analysis allowed for U.S. Food and Drug Administration approval of topiramate for initial monotherapy in pediatric patients (2-9 years).
Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Modelos Biológicos , Topiramato/administração & dosagem , Adolescente , Fatores Etários , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Simulação por Computador , Esquema de Medicação , Aprovação de Drogas , Epilepsia/sangue , Feminino , Humanos , Masculino , Fatores de Tempo , Topiramato/efeitos adversos , Topiramato/farmacocinética , Resultado do Tratamento , Estados Unidos , United States Food and Drug AdministrationRESUMO
Zonisamide is an antiepileptic drug developed and first marketed in Japan in 1989. Cases of oligohydrosis, characterized by deficient production and secretion of sweat, were reported in children treated with zonisamide in Japan during development and in the postmarketing period. Zonisamide was approved in the United States in March 2000 for adjunctive treatment of partial seizures in adults. Searching the Food and Drug Administration's Adverse Events Reporting System, we identified six domestic cases of zonisamide-associated oligohydrosis and/or fever, all in patients = 18 years of age. The calculated reporting rate was 13 cases per 10,000 pediatric-years of exposure, approximately 10-fold the reporting rate in Japan. A possible risk factor for the development of oligohydrosis in these cases was pediatric age, leading to exposure to elevated zonisamide blood levels relative to patient size. Although the mechanism for zonisamide-associated oligohydrosis has not been fully elucidated, the drug may mediate its effect on eccrine sweat glands by inhibiting carbonic anhydrase, thereby influencing pH dynamics, hydrogen ion concentration, and available calcium transients. Awareness of zonisamide-associated oligohydrosis may prevent morbidity, especially in the pediatric population.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Febre/induzido quimicamente , Hipo-Hidrose/induzido quimicamente , Isoxazóis/efeitos adversos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , ZonisamidaAssuntos
Anticonvulsivantes/efeitos adversos , Frutose/efeitos adversos , Glaucoma de Ângulo Fechado/induzido quimicamente , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Criança , Pré-Escolar , Rotulagem de Medicamentos , Feminino , Frutose/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Topiramato , Estados Unidos , United States Food and Drug AdministrationRESUMO
Parkinson's disease is an age-related degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions. Symptoms can include tremor, stiffness, slowness of movement, and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60. Presently, there is no precedent for approving any drug as having a modifying effect (i.e., slowing or delaying) for disease progression of Parkinson's disease. Clinical trial designs such as delayed start and withdrawal are being proposed to discern symptomatic and protective effects. The current work focused on understanding the features of delayed start design using prior knowledge from published and data submitted to US Food and Drug Administration (US FDA) as part of drug approval or protocol evaluation. Clinical trial simulations were conducted to evaluate the false-positive rate, power under a new statistical analysis methodology, and various scenarios leading to patient discontinuations from clinical trials. The outcome of this work is part of the ongoing discussion between the US FDA and the pharmaceutical industry on the standards required for demonstrating disease-modifying effect using delayed start design.