Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy

Carlos Alberto Calderon-Ospina; Jubby Marcela Galvez; Claudia López-Cabra; Natalia Morales; Carlos Martín Restrepo; Jesús Rodríguez; Fabio Ancízar Aristizábal-Gutiérrez; Alberto Velez-van-Meerbeke; Paul Laissue; Dora Janeth Fonseca-Mendoza

doi:10.3389/fphar.2020.00555

Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy

Título traducido de la contribución: Posibles determinantes genéticos de la respuesta a fenitoína en un grupo de pacientes colombianos con epilepsia

Carlos Alberto Calderon-Ospina
, Jubby Marcela Galvez
, Claudia López-Cabra
, Natalia Morales
, Carlos Martín Restrepo
, Jesús Rodríguez
, Fabio Ancízar Aristizábal-Gutiérrez
, Alberto Velez-van-Meerbeke
, Paul Laissue
, Dora Janeth Fonseca-Mendoza

Producción científica: Contribución a revista › Artículo de Investigación › revisión exhaustiva

17 Citas (Scopus)

Resumen

Antecedentes: la epilepsia es un problema de salud grave en todo el mundo. A pesar de la introducción de nuevos fármacos antiepilépticos (FAE), casi el 30% de estos pacientes tienen formas farmacorresistentes de la enfermedad (DRE), con un aumento significativo de la morbimortalidad. Objetivo: Nuestro objetivo fue evaluar el impacto de algunos factores genéticos y su posible asociación con la respuesta al tratamiento y las reacciones adversas a los medicamentos (RAM) para fenitoína en 67 pacientes colombianos adultos con epilepsia. Métodos: Realizamos un estudio de cohorte prospectivo, observacional y analítico para evaluar cuatro polimorfismos en farmacogenes: CYP2C9 * 2-c.430C> T (rs1799853), CYP2C9 * 3-c.1075A> C (rs1057910), ABCB1-c.3435T> C (rs1045642) y SCN1A-IVS5-91G> A (rs3812718) y su asociación con la respuesta al tratamiento. Los pacientes fueron seguidos durante 1 año para confirmar la existencia de DRE (no respuesta) y ADR utilizando un enfoque de farmacovigilancia, seguido de un consenso para clasificar las RAM según causalidad, prevenibilidad, intensidad y su relación con la dosis de fenitoína, la duración del tratamiento y los factores de susceptibilidad (metodología DoTS). Resultados: Un poco más de la mitad de los sujetos evaluados (52,2%) no respondieron a fenitoína. En cuanto a la correlación genotipo-fenotipo no hubo asociación entre polimorfismos de SCN1A y ABCB1 y DRE (no respuesta) (p = 0,34), ni con polimorfismos CYP2C9 y la aparición de RAM (p = 0,42). Solo encontramos una asociación entre alelos polimórficos de CYP2C9 y RAM vesíibulo-cerebelosas (mareos, ataxia, diplopía y disartria) (p = 0,001). Los alelos CYP2C9 * 2-c.430C> T y CYP2C9 * 3-c.1075A> C se identificaron como factores de susceptibilidad a las RAM en el 24% de los pacientes. Conclusiones: Los alelos funcionales disminuidos de CYP2C9 fueron altamente predictivos de reacciones adversas cerebelosas vestibulares a fenitoína en nuestro estudio (p = 0,001). Sin embargo, las variantes genéticas CYP2C9 * 2-c.430C> T, CYP2C9 * 3-c.1075A> C, ABCB1-c.3435T> C y SCN1A-IVS5- 91G> A, no se asociaron con la respuesta al tratamiento en nuestro estudio.

Título traducido de la contribución	Posibles determinantes genéticos de la respuesta a fenitoína en un grupo de pacientes colombianos con epilepsia
Idioma original	Inglés estadounidense
Número de artículo	555
Publicación	Frontiers in Pharmacology
Volumen	11
DOI	https://doi.org/10.3389/fphar.2020.00555
Estado	Publicada - may. 7 2020

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ODS 3: Salud y bienestar

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Farmacología
Farmacología (médica)

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Calderon-Ospina, C. A., Galvez, J. M., López-Cabra, C., Morales, N., Restrepo, C. M., Rodríguez, J., Aristizábal-Gutiérrez, F. A., Velez-van-Meerbeke, A., Laissue, P., & Fonseca-Mendoza, D. J. (2020). Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy. Frontiers in Pharmacology, 11, Artículo 555. https://doi.org/10.3389/fphar.2020.00555

@article{ec64af1c3800426191e038f3f09ba1d8,

title = "Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy",

abstract = "Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30\% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy. Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology). Results: A little more than half of evaluated subjects (52.2\%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24\% of patients. Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study.",

author = "Calderon-Ospina, \{Carlos Alberto\} and Galvez, \{Jubby Marcela\} and Claudia L{\'o}pez-Cabra and Natalia Morales and Restrepo, \{Carlos Mart{\'i}n\} and Jes{\'u}s Rodr{\'i}guez and Aristiz{\'a}bal-Guti{\'e}rrez, \{Fabio Anc{\'i}zar\} and Alberto Velez-van-Meerbeke and Paul Laissue and Fonseca-Mendoza, \{Dora Janeth\}",

year = "2020",

month = may,

day = "7",

doi = "10.3389/fphar.2020.00555",

language = "English (US)",

volume = "11",

journal = "Frontiers in Pharmacology",

issn = "1663-9812",

publisher = "Frontiers Media S. A.",

}

TY - JOUR

T1 - Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy

AU - Calderon-Ospina, Carlos Alberto

AU - Galvez, Jubby Marcela

AU - López-Cabra, Claudia

AU - Morales, Natalia

AU - Restrepo, Carlos Martín

AU - Rodríguez, Jesús

AU - Aristizábal-Gutiérrez, Fabio Ancízar

AU - Velez-van-Meerbeke, Alberto

AU - Laissue, Paul

AU - Fonseca-Mendoza, Dora Janeth

PY - 2020/5/7

Y1 - 2020/5/7

N2 - Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy. Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology). Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients. Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study.

AB - Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy. Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology). Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients. Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study.

UR - https://www.scopus.com/pages/publications/85085200819

UR - https://www.scopus.com/pages/publications/85085200819#tab=citedBy

U2 - 10.3389/fphar.2020.00555

DO - 10.3389/fphar.2020.00555

M3 - Research Article

C2 - 32457604

AN - SCOPUS:85085200819

SN - 1663-9812

VL - 11

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

M1 - 555

ER -

Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy

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