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XIMELAGATRAN: ACTUALIZACION SOBRE EL MECANISMO DE ACCION Y EL DESARROLLO CLINICO DEL PRIMER INHIBIDOR DIRECTO DE LA TROMBINA POR VIA ORAL

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El ximelagatran es el primer agente oral en la nueva clase de los inhibidores directos de la trombina; es un inhibidor potente de la actividad de la trombina, de su producción, de la activación plaquetaria y de la formación del trombo.
sarich9.jpg Autor:
Sarich, troy
Columnista Experto de SIIC

Institución:
AstraZeneca LP Wilmington, DE, USA

Artículos publicados por Sarich, troy
Coautores
Stig Boström*  Ulf Eriksson**  Michael Wolzt***  Christer Mattsson** 
PhD Professor. AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden*
PhD. AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden**
MD Clinical Pharmacology, Allgemeines Krankenhaus Wien, Medical University of Vienna, Vienna, Austria***
Recepción del artículo
23 de Junio, 2004 		Aprobación
30 de Junio, 2004
Primera edición
18 de Marzo, 2005 		Segunda edición, ampliada y corregida
7 de Junio, 2021

XIMELAGATRAN: ACTUALIZACION SOBRE EL MECANISMO DE ACCION Y EL DESARROLLO CLINICO DEL PRIMER INHIBIDOR DIRECTO DE LA TROMBINA POR VIA ORAL

Resumen
El ximelagatran es el primer agente oral de la nueva clase de inhibidores directos de la trombina, desarrollado para la prevención y el tratamiento de una variedad de trastornos tromboembólicos. Su forma activa, el melagatran, es un potente inhibidor de la actividad de la trombina in vitro (Ki = 2 nmol/l). Los estudios que investigaron el mecanismo de acción del melagatran demostraron la inhibición dependiente de la dosis de la generación de trombina, la activación plaquetaria y la formación de trombos ex vivo. La inhibición de la generación de trombina por este agente parece involucrar el bloqueo de la activación de retroalimentación del factor V por la trombina, mientras que la actividad antiagregante es indirecta a través de la inhibición de la activación plaquetaria inducida por la trombina. Luego de la administración oral de ximelagatran, la exposición al melagatran muestra baja variabilidad, se relaciona en forma lineal con la dosis y es estable con las administraciones reiteradas. El perfil farmacocinético y farmacodinámico es uniforme entre voluntarios sanos y diferentes grupos de pacientes, no se ve afectado por los alimentos y tiene un potencial bajo de interacciones con drogas que utilizan el sistema enzimático del citocromo P450. El perfil farmacocinético previsible y reproducible corroboró el desarrollo clínico del ximelagatran con regímenes con dosis fijas sin necesidad de titularlas o de monitorear la coagulación.

Palabras clave
Terapéutica anticoagulante, inhibidores directos de la trombina, mecanismo de acción, ximelagatran


Artículo completo
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XIMELAGATRAN: AN UPDATE ON THE MECHANISM OF ACTION AND CLINICAL DEVELOPMENT OF THE FIRST ORAL DIRECT THROMBIN INHIBITOR

Abstract
Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and has been developed for the prevention and treatment of a range of thromboembolic disorders. Its active form, melagatran, is a potent inhibitor of thrombin activity in vitro (Ki = 2 nmol/l). Studies investigating the mechanism of action of melagatran have demonstrated dose-dependent inhibition of thrombin generation, platelet activation and thrombus formation ex vivo. The inhibition of thrombin generation by melagatran appears to involve blockade of the feedback activation of factor V by thrombin, while the anti-aggregatory activity of melagatran on platelets is indirect via inhibition of thrombin-induced platelet activation. After oral administration of ximelagatran, melagatran exposure shows low variability, correlates linearly with dose and is stable with repeated dosing. The pharmacokinetic/pharmacodynamic profile for melagatran is consistent for healthy volunteers and different patient groups, unaffected by co-administration with food and has a low potential for drug:drug interactions mediated via the cytochrome P450 system. The predictable and reproducible pharmacokinetic profile has supported the clinical development of ximelagatran using fixed-dose regimens without dose-titration adjustments or coagulation monitoring.

Key words
Anticoagulant therapy, direct thrombin inhibitors, mechanism of action, ximelagatran


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Especialidades
Principal: Farmacología, Hematología
Relacionadas: Bioquímica, Cardiología, Diagnóstico por Laboratorio, Medicina Farmacéutica, Medicina Interna



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Sarich, Troy
Patrocinio y reconocimiento:
Agradecimiento: Los autores desean reconocer la asistencia de Ian Faulkner, PhD (MediTech Media, Reino Unido) por el apoyo editorial para el desarrollo de este artículo.
Bibliografía del artículo
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