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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00555

DOI=10.3389/fphar.2020.00555

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: <italic>CYP2C9*2-c.430C&gt;T</italic> (rs1799853), <italic>CYP2C9*3-c.1075A&gt;C</italic> (rs1057910), <italic>ABCB1-c.3435T&gt;C</italic> (rs1045642), and <italic>SCN1A-IVS5-91G&gt;A</italic> (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).</p></sec><sec><title>Results</title><p>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 <italic>SCN1A</italic> and <italic>ABCB1</italic> and DRE (non-response) (<italic>p</italic> = 0.34), and neither with <italic>CYP2C9</italic> polymorphisms and the occurrence of ADRs (<italic>p</italic> = 0.42). We only found an association between polymorphic alleles of <italic>CYP2C9</italic> and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (<italic>p</italic> = 0.001). Alleles <italic>CYP2C9*2-c.430C&gt;T</italic> and <italic>CYP2C9*3-c.1075A&gt;C</italic> were identified as susceptibility factors to ADRs in 24% of patients.</p></sec><sec><title>Conclusions</title><p>Decreased function alleles of <italic>CYP2C9</italic> were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (<italic>p</italic> = 0.001). However, the genetic variants <italic>CYP2C9*2-c.430C&gt;T</italic>, <italic>CYP2C9*3-c.1075A&gt;C</italic>, <italic>ABCB1-c.3435T&gt;C,</italic> and <italic>SCN1A-IVS5-91G&gt;A</italic>, were not associated with treatment response in our study.</p></sec>