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Tesis Egras Gaucher

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Tesis Egras Gaucher Diseño y grafismo de portada realizado por Laura Casagrande Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia Servici de Farmàcia - Hospital Universitari Dr. Peset de València Programa de Doctorat en Biomedicina i Farmàcia “MONITORIZACIÓN E INDIVIDUALIZACIÓN POSOLÓGICA DE GLUCOCEREBROSIDASA EN PACIENTES GAUCHER TIPO I” Memoria para optar al grado de Doctor realizada por Elena Gras Colomer Directores: Mónica Climente Martí, Matilde Merino Sanjuán València, marzo 2018 Doctorado en Biomedicina y Farmacia Tesis Doctoral de ELENA GRAS COLOMER Titulada: ”Monitorización e individualización posológica de glucocerebrosidasa en pacientes con enfermedad de Gaucher Tipo I” Lectura: 4 Mayo 2018 12,00 horas Sala Juntas Facultat de Farmàcia Universitat de València Directores/a Matilde Merino Sanjuán Mónica Climente Martí Departament de Farmàcia i Tecnologia Farmacèutica i Parasitologia Servici de Farmàcia - Hospital Dr. Peset de València Programa de Doctorat en Biomedicina i Farmàcia Las que suscriben, Dra. Mónica Climente Martí, Jefa del Servicio de Farmacia del Hospital Universitario Dr. Peset y profesora asociada del Departamento de Farmacia y Tecnología Farmacéutica y Parasitología y Dra. Matilde Merino Sanjuán catedrática del Departamento de Farmacia y Tecnología Farmacéutica y Parasitología. CERTIFICAN: que la Memoria para optar al grado de Doctor realizada por Elena Gras Colomer, cuyo título es: “MONITORIZACIÓN E INDIVIDUALIZACIÓN POSOLÓGICA DE GLUCOCEREBROSIDASA EN PACIENTES GAUCHER TIPO I” ha sido realizada bajo su dirección y reúne todos los requisitos para su juicio y calificación. Lo que suscriben en València, a 5 marzo 2018 Mónica Climente Martí Matilde Merino Sanjuán Este proyecto ha sido subvencionado por ! Fundación Genzyme mediante una beca para investigación en el campo de enfermedades de depósito lisosomal en 2012. ! Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) mediante un contrato predoctoral en investigación en enfermedades depósito lisosomal y mediante la convocatoria de ayudas para el fomento de la actividad investigadora de modalidad de grupos emergentes en 2015 (UGP-15- 222). Los resultados obtenidos en esta Tesis Doctoral han dado lugar a las siguientes publicaciones – Gras Colomer E, Martínez Gómez MA, González Álvarez A,Climente Martí M, León Moreno, P, Fernández Zarzoso M, Jiménez-Torres NV. ‘Development and application to clinical practice of a validated HPLC method for the analysis of B- glucocerebrosidase in Gaucher disease’. J Pharm Biomed Anal. 2014 Mar;91:123- 30. Doi: 10.1016/j.jpba.2013.12.027; Impact Factor: 2.829 Index JCR. – Gras-Colomer E, Martínez-Gómez MA, Moya-Gil A, Fernandez-Zarzoso M, Merino-Sanjuan M, Climente-Martí M. ‘Cellular Uptake of Glucocerebrosidase in Gaucher Patients Receiving Enzyme Replacement Treatment’. Clin Pharmacokinet. 2016 Sep;55(9):1103-13. Doi: 10.1007/s40262-016-0387-2; Impact Factor: 5.053 Index JCR. – Gras-Colomer E, Martínez-Gómez MA, Climente-Martí M, Fernandez-Zarzoso M, Almela-Tejedo M, Giner-Galvañ V, Marcos-Rodríguez JA, Rodríguez-Fernández A, Torralba-Cabeza MÁ, Merino-Sanjuan M. ‘Relationship between Glucocerebrosidase Activity and clinical response to Enzyme Replacement Therapy in patients with Gaucher Disease type I’. Basic Clin Pharmacol Toxicol. 2018 Feb 8. Doi: 10.1111/bcpt.12977; Impact Factor: 3.176. Index JCR. Agradecimientos AGRADECIMIENTOS Gracias a la Dra. Mónica Climente y a la Prof. Matilde Merino por vuestro compromiso y generosidad, por marcarme el camino y enseñarme a ser persistente, por vuestros consejos y ánimos infatigables, que han permitido hacer realidad esta tesis. Al Prof. N. Víctor Jiménez Torres, por proporcionarnos el mapa mental y encendernos la chispa de esta investigación; por transmitirme la pasión de la farmacia hospitalaria, la curiosidad científica y enseñarme a vivir ‘pericolosamente’. A la Dra. Mª Amparo Martínez por tu inmensa ayuda en toda la parte cromatográfica y por estar siempre dispuesta a nuevos retos. Al Dr. Víctor Mangas y al Dr. Javier Martínez Moreno por su ayuda y docencia en el modelado farmacocinético. Gracias a todos los profesionales del Servicio de Farmacia del Hospital Dr. Peset, por su compromiso con el paciente y por enseñarme día a día. Agradecer al servicio de Hematología del Hospital Dr. Peset su complicidad e implicación en el proyecto. Mi agradecimiento a todos los profesionales de los hospitales participantes por vuestra colaboración entusiasta, demostrando que la investigación independiente en red es posible. A mis amigos/as por vuestro cariño durante el tiempo que ha durado esta tesis. Gracias por esos vinos tan necesarios! Gracias a mi familia. A Óscar, por tu enorme apoyo y porque siempre sabes sacarme una sonrisa. Gracias a mamá, papá y Diego por cuidarme siempre, y por inculcarme la disciplina y la fuerza de voluntad que me han permitido llegar hasta aquí. A los pacientes por su generosidad ‘Apunta a construir catedrales porque te quedará una capilla preciosa’ Prof. N. Víctor Jiménez Torres Índice ÍNDICE ABREVIATURAS ....................................................................................................................... 5 PRÓLOGO. .................................................................................................................................. 7 RESUMEN. ............................................................................................................................... 11 1. INTRODUCCIÓN .................................................. .....................................................................13 1.1. LA ENFERMEDAD DE GAUCHER ...................................................................................... 13 1.1.1. Epidemiología ...........................................................................................................13 1.1.2. Aspectos bioquímicos ............................................................................................14 1.1.3. Aspectos genéticos ..................................................................................................16 1.1.4. Aspectos clínicos ......................................................................................................16 1.1.5. Diagnóstico de la enfermedad de Gaucher ....................................................17 1.1.6. Escalas de evaluación de la enfermedad ........................................................18 1.1.7. Biomarcadores ..........................................................................................................19 1.2. TRATAMIENTO DE LA ENFERMEDAD DE GAUCHER ............................................. 20 1.2.1. Terapia de Reducción de Sustrato ....................................................................20 1.2.2. Terapia Enzimática Sustitutiva (TES) ..............................................................21 1.3. ANÁLISIS FARMACOCINÉTICO .......................................................................................... 25 1.3.1. Determinación cuantitativa de la actividad enzimática de glucocerebrosidasa .............................................................................................................26 1.3.2. Farmacocinética de la terapia enzimática sustitutiva ...............................27 2. OBJETIVOS .................................................. ...............................................................................29 3. MATERIAL Y MÉTODOS .................................................. .....................................................30 3.1. DISEÑO ........................................................................................................................................ 30 3.2. POBLACIÓN A ESTUDIO ....................................................................................................... 31 3.3. ASPECTO ÉTICOS .................................................................................................................... 31 3.4. ESQUEMA DE TRATAMIENTO ........................................................................................... 32 3.5. VARIABLES ESTUDIADAS .................................................................................................... 32 3.5.1. Variables relacionadas con el paciente ...........................................................32 3.5.2. Variables relacionadas con la enfermedad ....................................................32 3.5.3. Variables relacionadas con la TES .....................................................................33 Monitorización e individualización posológica de glucocerebrosidasa en pacientes Gaucher tipo I 1 Índice 3.5.4. Variables relacionadas con la actividad enzimática de glucocerebrosidasa .............................................................................................................34 3.5.5. Variables relacionadas con la respuesta al tratamiento ...........................35 3.6. ANÁLISIS DE DATOS .............................................................................................................. 36 3.6.1. Métodos analíticos ..................................................................................................36 3.6.1.1. Método analítico de cuantificación de la glucococerebrosidasa lisosomal (GBA1) ............................................................................................................36 3.6.1.2. Método analítico de cuantificación de glucocerebrosidasa lisosomal y no lisosomal (GCase) .............................................................................36
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