1 UNIVERSIDAD SAN PABLO CEU FACULTAD DE MEDICINA CEINDO PROGRAMA DE DOCTORADO EN MEDICINA TRANSLACIONAL Estudio farmacogenético de polimorfismos de base única asociados a la toxicidad y eficacia de cabazitaxel en pacientes con cáncer de células uroteliales avanzado. Tesis doctoral Carlos Hagen
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UNIVERSIDAD SAN PABLO CEU FACULTAD DE MEDICINA CEINDO
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Paclitaxel unido a albúmina en formade nanopartículas. No requieresolventes. Liberación incrementada entejidostumorales.
Paclitaxelpoliglumex
‐Noaprobado Paclitaxel unido a polímero lo quereduce su toxicidad mientras aumentasusolubilidadyeficacia.
DHA‐paclitaxel
‐Noaprobado
Compuesto no tóxico en su formaconjugada. Acción citotóxica sólocuandoesmetabolizadoporeltumor.
Larotaxel ‐Noaprobado Derivado semisintético. No es sustratopara la P‐gp. Actividad en tumoresquimioresistentes. Capacidad paracruzarlabarrerahematoencefálica.
Ortotaxel ‐Noaprobado Derivado semisintético. No es sustratopara la P‐gp. Actividad en tumoresquimiorresistentes. Capacidad paracruzar la barrera hematoencefálica.Administraciónoral.
BMS‐184476 ‐Noaprobado Solubilidad incrementada. Mayorpotencia frente a tumoresquimiorresistentesoconmutacionesdelatubulina.
DJ‐927 ‐Noaprobado Mayor actividad que el docetaxel ypaclitaxel. Eficacia en tumoresquimiorresistentes. Administraciónoral.
Genexol‐PM ‐Noaprobado Paclitaxel en micelas poliméricas.Biodisponibilidad incrementada. Nonecesitasolventes
Transtornosde la sangreydelsistemalinfático –Otros,especificar.
Sin síntomas osíntomas leves.Observaciónclínicaodiagnóstica.Intervención noindicada.
Indicadaintervenciónmínima, moderadao no‐invasiva.Actividadesinstrumentales dela vida diarialimitadas segúnedad.
Severidad clínica omédica, pero noinmediatamenteamenazante para lavida. Hospitalizacióno extensión de lahospitalizaciónnecesaria.Invalidante,actividadesinstrumentales deautocuidadolimitadas.
3.1 Variación interindividual de la eficacia y la toxicidad
de fármacos.
La frecuenciadepacientesno respondedores a fármacosdeuso comúnoscila
entreun20%yun75%(100),mientrasque las reaccionesadversasa fármacos
(ADRsdel inglés,AdverseDrugReactions)suponenalrededordel7%detodos los
ingresos hospitalarios en países occidentales (101‐103). Además, la toxicidadcausada por fármacos tiene un impacto negativo en la calidad de vida de los
causalconlaeficaciaytoxicidadobservadas. Losestudiosdegenescandidatoshandemostrado ser una estrategia válida y eficaz para la identificación de variantes
‐Paciente‐ Fecha de consentimientoinformado‐Visita‐Fechadenacimiento‐Sexo‐Raza‐Pesoactual‐Talla‐Superficiecorporal‐Temperatura‐Presionsistolica‐Presiondiastolica‐Frecuenciacardiaca‐FEVI‐Fechadediagnostico‐Localizacion tumorprimario‐EstadioT‐EstadioN‐EstadioM‐Gradohistopatologico‐ Intervalo fin QT 1L hastaprogresión‐Estadofuncional(ECOG)‐ECOGMAYOR0(S/N)‐HbMENOR10g/l(S/N)‐Metástasishepáticas(S/N)‐Nºfactoresmalpronóstico‐FactorPronósticoGlobal
‐EventoAdverso‐Término‐LowLevelTerm‐PreferredTerm‐SOCterm‐Intensidad‐AEserio(S/N)‐Fechainicio‐Fechafin‐Evolucion‐Accióntomada‐ Relacion con elcompuesto(S/N)
rs11572080, rs1113129, ABCB1 rs1045642, rs1128503, rs2032582 y TUBB1
rs6070697,rs463312.
Resultados
48
Paciente G‐CSF CompuestoVia deadministración
DosisProfilaxis(P)vsTratamientoAE(T)
101 NO _ _ _ _102 SI Filgrastim SC 300mcg T/P103 SI Filgrastim SC 300mcg P104 NO _ _ _ _204 SI Filgrastim SC 300mcg P205 NO _ _ _ _301 NO _ _ _ _401 SI Filgrastim SC 300mcg T/P402 NO _ _ _ _403 NO _ _ _ _404 SI Filgrastim SC 300mcg T405 SI Filgrastim SC 300mcg P503 NO _ _ _ _803 NO _ _ _ _804 NO _ _ _ _901 SI Filgrastim PO 300mcg P902 SI Filgrastim SC 300mcg P903 SI Filgrastim SC 300mcg P904 NO _ _ _ _905 NO _ _ _ _1003 NO _ _ _ _1004 SI Nodisponible SC 263mcg T1201 NO _ _ _ _1301 NO _ _ _ _1304 SI Filgrastim PO 390mcg P1305 SI Filgrastim SC 335mcg P1307 NO _ _ _ _1402 NO _ _ _ _1404 NO _ _ _ _1405 NO _ _ _ _1501 SI Filgrastim PO 300mcg P1502 SI Filgrastim SC 300mcg P1602 NO _ _ _ _1801 SI Filgrastim SC 300mcg1802 NO _ _ _ _1803 NO _ _ _ _1804 SI Filgrastim SC 300mcg P2101 SI Filgrastim SC 480mcg P2202 NO _ _ _ _2401 NO _ _ _ _2402 NO _ _ _ _2403 NO _ _ _ _2404 NO _ _ _ _2405 SI Filgrastim SC ND T2406 NO _ _ _ _
Tabla8: UsodeG‐CSFen lospacientes incluidos en el estudio farmacogenético. Para cadapaciente se
Figura 7: Número de AE de grado ≥ 3 vs. genotipos para el SNP rs1045642 del gen ABCB1.El valor Pcorrespondealanálisisunivariante.LosresultadosdelanálisismultivariaantesepuedenverenlaTabla10.
Figura 8: Número de Aes de grado ≥ 3 vs. genotipos para el SNP rs1128503 del gen ABCB1. El valor Pcorrespondealanálisisunivariante.LosresultadosdelanálisismultivariantesepuedenverenlaTabla10.
0%
25%
50%
75%
100%
T/T C/T C/C
P=0,012
≥2AEs
0‐1AEs
0%
25%
50%
75%
100%
T/T C/T C/C
P=0,045
≥2AEs
0‐1AEs
ABCB1 rs1045642
NAEs≥Grado3
ABCB1rs1128503
NAEs≥Grado3
Resultados
53
Figura 9: Número de Aes de grado 3 vs. genotipos para el SNP rs2032582 del gen ABCB1. El valor Pcorrespondealanálisisunivariante.LosresultadosdelanálisismultivariantesepuedenverenlaTabla10.
3. Genotipos asociados a la eficacia de cabazitaxel. Demodosemejantealdelatoxicidad,dosdelosSNPsanalizadosmostraronuna
asociación significativa con alguna de las variables de eficacia definidas para el
estudio.
El aleloCYP3A5*3mostró una asociación estadísticamente significativa con la
PFS (p = 0.0032, análisis univariante; Tabla 11, Figura 10). Estos resultados no
en la optimización del tratamiento con este fármaco. No obstante, resultaría
necesario llevar a cabo estudios posteriores en cohortes independientes de
pacientes demayor tamañomuestral, homogéneas y que dispongan de extensas
basesdedatosclínicosasociadas.
69
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