Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros




Base de datos
Intervalo de año de publicación
1.
Clin Transl Sci ; 10(5): 404-411, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28727908

RESUMEN

GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Adulto , Anciano , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Determinación de Punto Final , Humanos , Análisis de los Mínimos Cuadrados , Persona de Mediana Edad , Modelos Biológicos , Prueba de Estudio Conceptual , Receptores Acoplados a Proteínas G/metabolismo , Resultado del Tratamiento
2.
Clin Pharmacol Ther ; 101(4): 519-530, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27943276

RESUMEN

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.


Asunto(s)
Proteínas Portadoras/metabolismo , Citocromo P-450 CYP3A/metabolismo , Combinación de Medicamentos , Interacciones Farmacológicas , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adulto , Área Bajo la Curva , Proteínas Portadoras/antagonistas & inhibidores , Línea Celular , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/enzimología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Femenino , Voluntarios Sanos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Farmacocinética , Distribución Tisular , Adulto Joven
3.
Clin Pharmacol Ther ; 92(2): 243-50, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22739139

RESUMEN

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.


Asunto(s)
Antieméticos/administración & dosificación , Antineoplásicos/efectos adversos , Encéfalo/efectos de los fármacos , Morfolinas/administración & dosificación , Náusea/prevención & control , Antagonistas del Receptor de Neuroquinina-1 , Vómitos/prevención & control , Adulto , Aprepitant , Encéfalo/diagnóstico por imagen , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Morfolinas/farmacocinética , Náusea/inducido químicamente , Tomografía de Emisión de Positrones , Profármacos , Receptores de Neuroquinina-1/metabolismo , Equivalencia Terapéutica , Vómitos/inducido químicamente , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA