{"id":91092,"date":"2024-08-22T22:58:38","date_gmt":"2024-08-22T22:58:38","guid":{"rendered":"https:\/\/msdconecta.co.cr\/es\/?post_type=therapeutic-area&p=91092"},"modified":"2024-10-18T22:38:29","modified_gmt":"2024-10-18T22:38:29","slug":"mecanismo-de-accion-pembrolizumab-wp-0677","status":"publish","type":"therapeutic-area","link":"https:\/\/msdconecta.co.cr\/es\/therapeutic-areas\/oncologia-wp-0641\/mecanismo-de-accion-pembrolizumab-wp-0677\/","title":{"rendered":"Mecanismo de acci\u00f3n Pembrolizumab"},"content":{"rendered":"
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\n \"Mecanismo\n <\/figure>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n\n\n

Mecanismo de acci\u00f3n: Pembrolizumab<\/strong><\/p>\n\n\n

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El pembrolizumab, es un medicamento oncol\u00f3gico basado en la inmunoterapia que se comercializa con el nombre de Keytruda<\/strong> y que est\u00e1 aprobado en monoterapia o en combinaci\u00f3n con otras estrategias terap\u00e9uticas para el tratamiento de una variedad de tumores, entre ellos, el melanoma, el c\u00e1ncer de pulm\u00f3n de c\u00e9lulas no microc\u00edticas y el c\u00e1ncer urotelial.1<\/sup><\/p>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n\n\n

Los puntos de chequeo inmune<\/strong>2<\/strong><\/sup><\/p>\n\n\n\n

Son puntos que brindan retroalimentaci\u00f3n al sistema inmune para limitar la funci\u00f3n efectora y expansiva de los linfocitos T y juegan un papel importante en la tolerancia a auto ant\u00edgenos y permiten una regulaci\u00f3n fina de la respuesta de las c\u00e9lulas T. 2<\/sup><\/p>\n\n\n\n

El CTLA-4 (ant\u00edgeno asociado a los linfocitos citot\u00f3xicos) es un regulador negativo de la respuesta inmune cuya activaci\u00f3n reduce la funci\u00f3n de las c\u00e9lulas T mediante una variedad de mecanismos.3<\/sup> Otro de los puntos de chequeo inmune, es el mediado por el PD-1 (programmed<\/em> cell death protein 1<\/em>), un receptor transmembrana activado por sus ligandos PDL-1 y PDL-2.<\/p>\n\n\n

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Expresi\u00f3n del sistema PD-1<\/strong><\/p>\n\n<\/div>\n\n\n

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PD1 se<\/strong> expresa en:4<\/sup><\/strong><\/p>\n\n<\/div>\n\n\n

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C\u00e9lulas CD4+, CD8+, T, B, citot\u00f3xicas (NK). Macr\u00f3fagos y dendr\u00edticas activadas.<\/p>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n<\/div>\n\n\n

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PDL-1 se<\/strong> constitutivamente expresa en:4<\/sup><\/strong><\/p>\n\n<\/div>\n\n\n

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C\u00e9lulas T, B, dendr\u00edticas, CD4+, CD25+ reguladoras C\u00e9lulas epiteliales, c\u00e9lulas no hematopoy\u00e9ticas (estimulado por interfer\u00f3n \u0263)<\/p>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n<\/div>\n\n\n

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PDL-2 se expresa en:4<\/sup><\/strong><\/p>\n\n<\/div>\n\n\n

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Macr\u00f3fagos, c\u00e9lulas dendr\u00edticas (estimulado por interfer\u00f3n \u0263 e interleucina 4)<\/p>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n\n\n

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Papel de la v\u00eda PD-1 en la evasi\u00f3n tumoral inmune (2,3)<\/strong><\/p>\n\n\n\n

PDL-1 se sobreexpresa en las c\u00e9lulas neopl\u00e1sicas de diferentes c\u00e1nceres (debido a aberraciones gen\u00e9ticas y activaci\u00f3n de v\u00edas intracelulares que aumentan su expresi\u00f3n y a mecanismos adaptativos que inducen su expresi\u00f3n en el microambiente tumoral) y su uni\u00f3n a PD-1 en las c\u00e9lulas T lleva a inhibici\u00f3n de su funci\u00f3n evadiendo el ataque inmune.2<\/sup> Una vez activado por sus ligandos, mediante una actividad de fosfatasa, PD-1 inhibe las v\u00edas de se\u00f1alizaci\u00f3n de cinasas que normalmente llevar\u00edan a la activaci\u00f3n de la c\u00e9lula T. Adicionalmente, como se trata de un receptor transmembrana existe un mecanismo potencial que conducir\u00eda a la supervivencia de las c\u00e9lulas tumorales mediante se\u00f1alizaci\u00f3n reversa a trav\u00e9s de PDL-1 dentro de las c\u00e9lulas tumorales lo que llevar\u00eda a resistencia a su muerte inducida por linfocitos citot\u00f3xicos y otros mecanismos.2<\/sup><\/p>\n\n\n

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\n \"Mecanismo\n <\/figure>\n\n\n\n

La activaci\u00f3n normal de PD-1 por PDL-1 y PDL-2 en el n\u00f3dulo linf\u00e1tico regula la actividad de las c\u00e9lulas T por intermedio de la c\u00e9lula dendr\u00edtica y mediante la interacci\u00f3n de B7 con PDL-1. En el ambiente tumoral los PDL-1 expresados por por las c\u00e9lulas malignas en las c\u00e9lulas T suprimen la funci\u00f3n efectora de dichas c\u00e9lulas. Adaptado de 3.<\/strong><\/p>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n\n\n

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Mecanismo de acci\u00f3n de pembrolizumab2,4<\/sup><\/strong><\/p>\n\n\n\n

Pembrolizumab es un anticuerpo monoclonal humanizado IgG4 k que se une al receptor PD-1 en las c\u00e9lulas T, bloqueando su interacci\u00f3n con PD-L1 y PD-L2. La uni\u00f3n de pembrolizumab a PD-1 no activa los receptores Fc o el complemento, de modo que quede desprovisto de cualquier actividad citot\u00f3xica.2<\/sup><\/p>\n\n\n\n

La uni\u00f3n de pembrolizumab a PD-1 impide la activaci\u00f3n del receptor mediante la uni\u00f3n de sus ligandos naturales PDL-1 y PDL-2 y por tanto libera la acci\u00f3n citot\u00f3xica de los linfocitos T, esto restaura la capacidad del sistema inmunitario para eliminar las c\u00e9lulas cancerosas (figura<\/strong>).2<\/sup><\/p>\n\n\n\n

El bloqueo de PD-1 tambi\u00e9n puede aumentar la actividad de otras c\u00e9lulas inmunes, como las c\u00e9lulas T auxiliares y las c\u00e9lulas NK, potenciando a\u00fan m\u00e1s la respuesta contra el tumor.4<\/sup><\/p>\n\n\n

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\n \"Mecanismo\n <\/figure>\n\n<\/div>\n\n\n
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\n \"Mecanismo\n <\/figure>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n<\/div>\n\n <\/div>\n\n <\/div>\n\n\n\n

Perfil farmacin\u00e9tico de pembrolizumab 2:2F<\/strong><\/p>\n\n\n\n

La concentraci\u00f3n inhibidora efectiva del 50% en ensayos de activaci\u00f3n de c\u00e9lulas T oscila entre 0,1 y 0,3 nM. Es un polvo liofilizado y reconstituido en soluci\u00f3n de cloruro de sodio al 0,9% soluci\u00f3n hasta una concentraci\u00f3n final de 1 a 10 mg\/ml para administraci\u00f3n intravenosa. Es estable durante 4 horas a temperatura ambiente y 24 horas en refrigeraci\u00f3n y se administra en infusi\u00f3n intravenosa de 30 minutos.2<\/sup><\/p>\n\n\n\n

En estudios farmacocin\u00e9ticos, pembrolizumab mostr\u00f3 un efecto proporcional a la dosis. Aumento de las concentraciones m\u00e1ximas y m\u00ednimas, y curva de \u00e1rea bajo la concentraci\u00f3n plasm\u00e1tica-tiempo en estado estacionario (AUC). La depuraci\u00f3n del medicamento aumenta con el peso corporal. Por lo tanto, una base de peso la dosificaci\u00f3n compensa las variaciones en la exposici\u00f3n debidas a diferencias en peso. Basado en dosis de 1 a 10 mg\/kg cada 2 semanas o 2 a 10 mg\/kg cada 3 semanas, la depuraci\u00f3n de pembrolizumab es de 0,22 L\/d\u00eda y la vida media s\u00e9rica es de 26 d. La depuraci\u00f3n aumenta con el peso corporal, de modo que las concentraciones en estado estacionario de pembrolizumab se alcanzan a las 18 semanas, mientras que en un r\u00e9gimen de 3 semanas r\u00e9gimen de dosificaci\u00f3n.2<\/sup><\/p>\n\n\n

\n \n Acceder o inscribirme a Oncologia- Keytruda para ver m\u00e1s informaci\u00f3n<\/span>\n <\/a><\/div>\n\n\n\n
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Referencias<\/strong><\/p>\n\n\n\n

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  1. Keytruda. Pembrolizumab. Informaci\u00f3n para prescribir. MK3475-CENA-2019 020289. <\/li>
  2. Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother. 2016 Nov;12(11):2777-2789. doi: 10.1080\/21645515.2016.1199310. Epub 2016 Jul 11. PMID: 27398650; PMCID: PMC5137544. <\/li>
  3. Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 2015 Jun 10;33(17):1974-82. doi: 10.1200\/JCO.2014.59.4358. Epub 2015 Jan 20. PMID: 25605845; PMCID: PMC4980573.<\/li>
  4. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018 May 25;360(6382):1078-1080.<\/li><\/ol>\n\n\n\n
    <\/div>\n\n\n\n
    \n","protected":false},"excerpt":{"rendered":"

    Mecanismo de acci\u00f3n: Pembrolizumab Los puntos de chequeo inmune2 Son puntos que brindan retroalimentaci\u00f3n al sistema inmune para limitar la 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