Asunto(s)
Compuestos Heterocíclicos con 3 Anillos , Piperazinas , Animales , Femenino , Ratones , Oxazinas , Embarazo , PiridonasRESUMEN
AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety/tolerability of blocking reuptake of bile acids using the inhibitor GSK2330672 (GSK672) in patients with type 2 diabetes (T2D). METHODS: Subjects with T2D taking metformin were enrolled in two studies in which they took metformin 850 mg twice daily for 2 weeks prior to and during the randomized treatment periods. In the first crossover study (n = 15), subjects received GSK672 45 mg, escalating to 90 mg, twice daily, or placebo for 7 days. The second parallel-group study (n = 75) investigated GSK672 10-90 mg twice daily, placebo or sitagliptin for 14 days. RESULTS: In both studies, GSK672 reduced circulating bile acids and increased serum 7-α-hydroxy-4-cholesten-3-one (C4), an intermediate in the hepatic synthesis of bile acids. Compared with placebo, in the parallel-group study 90 mg GSK672 twice daily reduced fasting plasma glucose [FPG; -1.21 mmol/l; 95% confidence interval (CI) -2.14, -0.28] and weighted-mean glucose area under the curve (AUC)0-24 h (-1.33 mmol/l; 95% CI -2.30, -0.36), as well as fasting and weighted-mean insulin AUC0 -24 h . GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was â¼40%. There was no change in HDL cholesterol but there was a trend towards increased fasting triglyceride levels in the GSK672 groups compared with placebo. In both studies, the most common adverse events associated with GSK672 were gastrointestinal, mostly diarrhoea (22-100%), which appeared to be independent of dose. CONCLUSIONS: In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Metilaminas/administración & dosificación , Tiazepinas/administración & dosificación , Adulto , Apolipoproteínas B/metabolismo , Área Bajo la Curva , Ácidos y Sales Biliares/metabolismo , Glucemia/metabolismo , LDL-Colesterol , Estudios Cruzados , Diarrea/inducido químicamente , Método Doble Ciego , Esquema de Medicación , Ayuno/metabolismo , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Insulina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Metformina/efectos adversos , Metformina/farmacología , Metilaminas/efectos adversos , Metilaminas/farmacología , Persona de Mediana Edad , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidores , Tiazepinas/efectos adversos , Tiazepinas/farmacología , Resultado del TratamientoRESUMEN
The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.
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Fármacos Cardiovasculares/metabolismo , Digoxina/metabolismo , Proteínas de Transporte de Membrana/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacocinética , Digoxina/efectos adversos , Digoxina/farmacocinética , Interacciones Farmacológicas , Humanos , Proteínas de Transporte de Membrana/metabolismo , Modelos Biológicos , Seguridad del Paciente , Medición de Riesgo , Factores de RiesgoRESUMEN
High-dose ketoconazole (400 mg q.d. for ≥5 days) has been the gold-standard strong cytochrome P450 3A (CYP3A) inhibitor in drug development drug-drug interaction (DDI) studies. In 2013, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) advised against using this ketoconazole regimen following review of clinical safety reports. We systematically evaluated 19 strong CYP3A inhibitors from regulatory guidances and a literature database to identify itraconazole (200 mg b.i.d. on day 1, q.d. on days 2-6) and clarithromycin (500 mg b.i.d. for 7 days) as acceptable ketoconazole alternatives.
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Claritromicina/farmacología , Inhibidores del Citocromo P-450 CYP3A , Itraconazol/farmacología , Cetoconazol/farmacología , Claritromicina/administración & dosificación , Citocromo P-450 CYP3A , Bases de Datos Factuales , Diseño de Fármacos , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Europa (Continente) , Humanos , Itraconazol/administración & dosificación , Cetoconazol/administración & dosificación , Cetoconazol/efectos adversos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Drug interactions due to efflux transport inhibition at the blood-brain barrier (BBB) have been receiving increasing scrutiny because of the theoretical possibility of adverse central nervous system (CNS) effects identified in preclinical studies. In this review, evidence from pharmacokinetic, pharmacodynamic, imaging, pharmacogenetic, and pharmacovigilance studies, along with drug safety reports, is presented supporting a low probability of modulating transporters at the human BBB by currently marketed drugs.
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Barrera Hematoencefálica/metabolismo , Interacciones Farmacológicas , Proteínas de Transporte de Membrana/metabolismo , Preparaciones Farmacéuticas , Transporte Biológico/fisiología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , FarmacocinéticaRESUMEN
This white paper provides a critical analysis of methods for estimating transporter kinetics and recommendations on proper parameter calculation in various experimental systems. Rational interpretation of transporter-knockout animal findings and application of static and dynamic physiologically based modeling approaches for prediction of human transporter-mediated pharmacokinetics and drug-drug interactions (DDIs) are presented. The objective is to provide appropriate guidance for the use of in vitro, in vivo, and modeling tools in translational transporter science.
Asunto(s)
Interacciones Farmacológicas , Proteínas de Transporte de Membrana/metabolismo , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Animales , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Encéfalo/metabolismo , Guías como Asunto , Humanos , Riñón/metabolismo , Hígado/metabolismo , Modelos Biológicos , Distribución TisularRESUMEN
The Second International Transporter Consortium (ITC) Workshop was held with the purpose of expanding on previous white-paper recommendations, discussing recent regulatory draft guidance documents on transporter-drug interactions, and highlighting transporter-related challenges in drug development. Specific goals were to discuss additional clinically relevant transporters (MATEs, MRP2, BSEP) and best-practice methodologies and to re-evaluate ITC decision trees based on actual case studies. The outcome of the workshop will be a series of white papers targeted for publication in 2013.