metricas
covid
Buscar en
Neurología (English Edition)
Toda la web
Inicio Neurología (English Edition) Pharmacogenetics of adverse reactions to antiepileptic drugs
Información de la revista
Vol. 33. Núm. 3.
Páginas 165-176 (abril 2018)
Visitas
5566
Vol. 33. Núm. 3.
Páginas 165-176 (abril 2018)
Review article
Open Access
Pharmacogenetics of adverse reactions to antiepileptic drugs
Farmacogenética de reacciones adversas a fármacos antiepilépticos
Visitas
5566
I. Fricke-Galindoa, H. Jung-Cookb, A. LLerenac, M. López-Lópezd,
Autor para correspondencia
mlopez@correo.xoc.uam.mx

Corresponding author.
a Programa de Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, México, D.F., Mexico
b Departamento de Neuropsicofarmacología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Departamento de Farmacia, Universidad Nacional Autónoma de México, Tlalpan, México, D.F., Mexico
c CICAB Centro de Investigación Clínica, Complejo Hospitalario Universitario y Facultad de Medicina, Universidad de Extremadura, Servicio Extremeño de Salud, Badajoz, Spain
d Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, México, D.F., Mexico
Este artículo ha recibido

Under a Creative Commons license
Información del artículo
Resumen
Texto completo
Bibliografía
Descargar PDF
Estadísticas
Figuras (2)
Tablas (4)
Table 1. Classification of adverse drug reactions.
Table 2. Frequent and very frequenta adverse reactions to antiepileptic drugs.16-31
Table 3. CYP2C9 and CYP2C19 variants associated with the presence of dose-dependent adverse reactions to phenytoin.
Table 4. HLA alleles associated with cutaneous adverse reactions caused by antiepileptic drugs.a
Mostrar másMostrar menos
Abstract
Introduction

Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients’ quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs.

Development

To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs.

Conclusions

Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy.

Keywords:
Pharmacogenetics
Adverse drug reactions
Antiepileptic drugs
CYP2C9
ABCC2
Human leukocyte antigen (HLA)
Resumen
Introducción

Las reacciones adversas a medicamentos (RAM) son un problema de salud pública y una importante causa de morbimortalidad a nivel mundial. En el caso de los fármacos antiepilépticos (FAE), la presencia de RAM puede ser un impedimento para lograr el éxito terapéutico al dificultar la adherencia al tratamiento e impactar la calidad de vida del paciente. La farmacogenética busca la identificación de variantes genéticas asociadas a la seguridad de los fármacos. En este artículo se revisan los genes que codifican para enzimas metabolizadoras y transportadores de fármacos, así como en el sistema HLA asociados a RAM inducidas por FAE.

Desarrollo

A la fecha, se ha reportado la asociación de los alelos CYP2C9*2 y *3, que codifican para enzimas de actividad reducida, con efectos neurotóxicos por fenitoína (PHT); alelos nulos de GSTM1 asociados con hepatotoxicidad inducida por carbamazepina (CBZ) y ácido valproico (VPA); polimorfismos genéticos de EPHX1 en la teratogénesis inducida por PHT; variantes genéticas de ABCC2 asociadas con RAM neurológicas por CBZ y VPA, y también diversos alelos de HLA (p. ej., HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) asociados con RAM de tipo cutáneas.

Conclusiones

Los hallazgos publicados muestran que existen RAM con base farmacogenética con una alta variabilidad interétnica, lo que refleja la necesidad de que se realicen estudios en distintas poblaciones para poder obtener resultados que sean de utilidad a un número mayor de pacientes. La búsqueda de biomarcadores que permitan la predicción de RAM a FAE podría mejorar la farmacoterapia en la epilepsia.

Palabras clave:
Farmacogenética
Reacciones adversas a medicamentos
Fármacos antiepilépticos
CYP2C9
ABCC2
Antígeno leucocitario humano (HLA)
Texto completo
Introduction

Pharmacogenetics emerged as a discipline in the 1950s, as a result of several observations of inherited enzymatic deficiencies causing drug toxicity in a specific group of patients. Its main objective has been the study of genetic variations associated with differences in the individual response to drugs.1,2

Pharmacogenetic studies analyse the association of gene allele variants which code for drug metabolising enzymes (DME) and drug transporters and receptors. They also analyse dosage requirements, effectiveness, and presence of adverse drug reactions (ADR). This review focuses on pharmacogenetic advances in the field of ADRs caused by antiepileptic drugs (AED), due to their impact on treatment adherence and quality of life in epileptic patients.

Adverse drug reactions

Adverse drug reactions are a serious problem for patients and public health systems. Incidence of ADRs is estimated at 6.73% in the USA3 and 6.5% in the United Kingdom,4 whereas in Switzerland they represent 3% of deaths.5 ADR prevalence has increased in patients older than 60 years.6 Patients with ADRs may need to be hospitalised or require longer admission times, which increases treatment costs.7-9

For more than 40 years, the World Health Organization has defined ADRs as “a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function”.10 Researchers have mentioned the need for a new definition to include ADRs caused by medication error, unauthorised use, misuse, and abuse of medicinal products, and the management of ADRs, which includes, for example, the administration of a specific treatment, total discontinuation of the drug, and future precautionary measures, among other considerations.11 Different types of reactions are classified from A to F, with A and B being the most common types. The characteristics of each type are listed in Table 1.11-13

Table 1.

Classification of adverse drug reactions.

ADR type  Characteristics  Examples of AED-induced ADRs 
Dose-dependent; excessive pharmacological response; predictable, reversible, frequent; low severity  Dizziness, headache, tremor, somnolence, insomnia, vertigo, ataxia, diplopia, depression, hyponaetremia, paraesthesias, gastrointestinal disorders 
Unrelated to dose or pharmacological mechanism of action; related to individual vulnerability; unpredictable; not frequent, high morbidity and mortality rates; reversible  Cutaneous and hypersensitivity reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, mild maculopapular exanthema, etc.), hepatotoxicity, aplastic anaemia, agranulocytosis 
Related to dose and time (dose accumulation); not frequent; chronic; most are reversible  Weight gain or loss, gingival enlargement, vision loss 
Related to time, usually to dose and prenatal exposure; not frequent; irreversible  Teratogenesis 
Related to drug withdrawal  Insomnia, anxiety, and disturbances after sudden withdrawal of benzodiazepines 
Unexpected treatment failure; frequent; related to dose and drug interaction  Decreased plasma levels of drugs due to enzyme induction of concomitant treatment 

AED: antiepileptic drug; ADR: adverse drug reaction.

Taken from Edwards and Aronson,11 Scott and Thompson,12 and Perucca and Gilliam.13

Adverse reactions to antiepileptic drugs

Epilepsy is one of the most prevalent neurological disorders globally, affecting approximately 70 million people worldwide and at least 5 million in Latin America.14,15

Despite numerous attempts to develop safe, harmless drugs, ADRs are unavoidable. The different mechanisms of action of AEDs may cause undesired effects; these are mainly neurological and psychiatric, although other organs and systems may also be affected (Table 2).16-31

Table 2.

Frequent and very frequenta adverse reactions to antiepileptic drugs.16-31

Antiepileptic drug  Type of adverse reaction
  Neurological  Cutaneous  Other 
Eslicarbazepine acetate  Dizziness, somnolence, headache, insomnia, tremor, diplopia, instability, behavioural disorders, and learning disabilities  MPE  Hyponatraemia, anorexia, nausea, vomiting, diarrhoea 
Valproic acid  Loss of memory, tremor  MPEb  Weight gain, hepatotoxicityb, teratogenesisb 
Carbamazepine  Loss of memory, dizziness, somnolence, instability  SJS, TEN, DRESS, HSS  Hyponatraemia, nausea, vomiting, teratogenesisb 
Clobazam  Somnolence, dizziness, irritability, ataxia, vertigo, headache  NR  Hypersalivation, weight gain 
Clonazepam  Somnolence, dizziness, ataxia, loss of memory, depression  NR  Upper respiratory tract infection, sinusitis 
Ethosuximide  Somnolence, ataxia, headache, difficulty concentrating  NR  Nausea, vomiting, leukopoenia, indigestion, diarrhoea, weight loss, hiccups, anorexia 
Phenytoin  Somnolence, loss of memory, mood swings  SJS, TEN, DRESS, HSS  Gingival hyperplasia, hirsutism, teratogenesisb 
Phenobarbital  Somnolence, dizziness, loss of memory, mood swings  MPEb, SJSb, TENb  NR 
Gabapentin  Somnolence, dizziness, ataxia  DRESSb  Joint pain, muscle pain, dry mouth, nausea, diarrhoea, peripheral oedema 
Lacosamide  Dizziness, ataxia, diplopia, vertigo, ataxia, tremor, headache  MPEb  Nausea, vomiting 
Lamotrigine  Loss of memory, somnolence, dizziness, ataxia, diplopia, headache  SJS, TEN, MPE  Rhinitis, nausea, teratogenesisb 
Levetiracetam  Somnolence, depression, diplopia, dizziness, fatigue, headache, depression, nervousness  SSJb  Pharyngitis 
Oxcarbazepine  Loss of memory, somnolence, headache, diplopia, fatigue  SJS, TEN, DRESS, HSS  Nausea, vomiting, hyponatraemia 
Perampanel  Dizziness, ataxia, somnolence, irritability  MPEb  Weight gain 
Pregabalin  Dizziness, somnolence, vertigo, blurred vision, difficulty concentrating, ataxia, fatigue  MPE  Dry mouth, oedema, weight gain 
Topiramate  Somnolence, dizziness, fatigue, learning difficulties, instability, paraesthesias, difficulty concentrating, difficulty speaking  MPE  Anorexia, weight loss, nephrolithiasis 
Zonisamide  Irritability, confusion, ataxia, dizziness, depression, difficulty concentrating  SJS, TEN, MPE  Nephrolithiasis, anorexia, weight loss 

DRESS: drug reaction with eosinophilia and systemic symptoms; HSS: hypersensitivity syndrome; MPE: maculopapular exanthema; NR: reactions not frequently reported for these antiepileptic drugs; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis.

a

Frequent reactions were those manifesting in ≥1/100 to <1/10 of the patients, and very frequent reactions, those reported by ≥1/10 patients.

b

These adverse reactions manifest at a frequency of ≥1/100; however, they were included due to their severity and their significance in pharmacogentics.

Taken from Brogden et al.,16 Greenwood,17 Herranz et al.,18 Hill et al.,19 Jarernsiripornkul et al.,20 Ketter et al.,21 Massot et al.,22 Pellock,23 Posner et al.,24 Tomson and Battino,25 Riverol et al.,26 Zaccara et al.27-31

ADRs during AED treatment complicate seizure control and adherence, and contribute to treatment withdrawal in 25% of patients.32-34 In addition to affecting the patient's quality of life,13,35 there is also an economic burden associated with ADRs.36

Pharmacogenetic research assesses the participation of genetic polymorphisms in response variability and susceptibility to specific types of ADR.2,37 The study of these polymorphisms is focused on genes coding for DMEs, AED transporters, and, more recently, on the genes of the human leukocyte antigen (HLA) system.2,38-40

Genetic polymorphisms in drug-metabolising enzymes associated with adverse reactions to antiepileptic drugsPhase I enzymes

Type A ADRs due to AEDs include neurological and psychiatric effects, vitamin deficiency, endocrine disorders, and hyponatraemia, among others.41 Since these ADRs are dose-dependent, their presence has been associated with polymorphisms in genes coding for DMEs and drug transporters.

These enzymes are mainly responsible for metabolising endogenous and exogenous compounds. For AEDs, metabolic reactions are catalysed predominantly by cytochrome P450 (CYP) enzymes in phase I metabolism and UDP-glucuronosyltransferase (UGT) enzymes in phase II.42 Two CYP enzymes, CYP2C9 and CYP2C19, are important in the metabolism of phenytoin (PHT), a drug with a narrow therapeutic window and nonlinear pharmacokinetics. CYP2C9 is responsible for 90% of PHT metabolism, while CYP2C19 is responsible for the remaining 10%. Polymorphisms in the genes coding for these cytochromes have been reported to be associated with different ADRs, especially neurological effects. Several allelic variants of CYP2C9 have been described; the 3 most representative and most frequently observed in white subjects are wild-type CYP2C9*1 (Arg144Ile359), CYP2C9*2 (Cys144Ile359), and CYP2C9*3 (Arg144Leu359). The latter 2 variants code for enzymes with decreased activity. Carriers of the CYP2C9*2 genotype present an enzymatic activity of 12% with regards to the wild-type CYP2C9*1, whereas enzymatic activity is only 5% in CYP2C9*3 carriers. In the Spanish population, frequency of CYP2C9*2 and CYP2C9*3 is 16% and 10%, respectively,43 whereas lower frequencies are observed in Chinese and African-American populations, as well as in Mexican mestizo and Mexican indigenous populations.44-46 Studies of African-American populations identified 2 alleles with decreased enzymatic activity: CYP2C9*5 (Ile359Thr) and *6 (c.delA818).47,48 This is important since carriers of these alleles present a poor metaboliser phenotype for PHT, which may cause dizziness, nystagmus, ataxia, excessive sedation, altered level of consciousness, and mental confusion, negatively impacting the patient's quality of life and treatment adherence.49,50 Several reports have described this association (Table 3); however, more studies into different populations, including from Latin America, are necessary to identify the reduced-activity variants specific to each population.

Table 3.

CYP2C9 and CYP2C19 variants associated with the presence of dose-dependent adverse reactions to phenytoin.

CYP2C9 genotype  CYP2C19 genotype  Population  Assessed phenotype  ADR  Type of study  Reference 
*6/*6  *1/*1  African-American  Neurotoxicity
Half-life (13 days), clearance (17% of that observed in other patients with normal enzymatic activity) 
Mental confusion, dysarthria, loss of memory, astasia  Case report  Kidd et al.48 
*1/*2
or *3 
US  White  Drug response  All types of ADRs  Pharmacogenetic study  Depondt et al.49 
*2/*2  *1/*4  White  Neurotoxicity and Pl (69μg/mL)a  Vertigo, ataxia, nystagmus, sedation  Case report  Dorado et al.50 
*3/*3  UD  Indian  Toxicity  Gingival enlargement  Case report  Babu et al.51 
*1/*3  *1/*3  Japanese  Pl (32.6μg/mL)a  Ataxia, diplopia  Case report  Ninomiya et al.52 
*3/*3  UD  Indian  Toxicity and Pl (33.2μg/mL)a  Nystagmus, ataxia, sedation, hirsutism, lymphadenopathy, anaemia, gingival enlargement  Case report  Ramasamy et al.53 

Pl: plasma levels; UD: undetermined; US: unspecified; ADR: adverse drug reaction.

a

Therapeutic range: 10-20μg/mL.

Although the Food and Drug Administration (FDA, the regulatory agency in the USA) has not included CYP2C9 polymorphisms in the list of pharmacogenetic biomarkers for PHT response, decreasing the dose prescribed to carriers of one or 2 alleles with decreased enzymatic activity has been considered important, as has monitoring the presence of ADRs and PHT plasma levels.54CYP2C19 also participates in PHT metabolism, although to a lesser extent. CYP2C19 alleles *2A, *2B, *2, *3, *4, *5A, *5B, *6, *7, and *8 present deficient enzymatic activity, potentially increasing the likelihood of toxic effects caused by PHT; however, these have received less study.55,56

Phenytoin metabolism mediated by CYP2C9 and CYP2C19 causes an epoxide type intermediate, which is inactivated by microsomal epoxide hydrolase (EPHX1).57 One study suggested that the teratogenic effects of PHT are due to the formation of this epoxide.58 A study of maternal EPHX1 polymorphisms in women treated with PHT and their children found that the EPHX1 113H and 139R polymorphisms were more frequent in mothers of children with congenital craniofacial abnormalities. Researchers also observed that the maternal EPHX1 Y113/H139 haplotype showed a significant protective effect against craniofacial abnormalities in pregnancies where the mother was receiving PHT.59

Phase II enzymes

The glutathione S-transferase (GST) superfamily of phase II enzymes also participates in AED metabolism. Their participation is important in the biotransformation of carbamazepine (CBZ) into the metabolites responsible for ADRs, such as carbamazepine-10,11-epoxide, arene oxides, and iminoquinones.60 A study in a Japanese population found an association between GSTM1 null alleles and increased levels of alanine aminotransferase and aspartate transaminase in patients treated with CBZ. This finding is associated with CBZ-induced hepatotoxicity, an idiosyncratic and unpredictable ADR which can cause irreversible damage.61 A retrospective study in Japanese patients receiving valproic acid (VPA) reported higher levels of γ-glutamyltransferase in carriers of GSTM1 null alleles.62 Both associations should be confirmed in Japanese and other populations to corroborate the clinical involvement of the GSTM1 null allele in the hepatic damage caused by CBZ and/or VPA.

UGT enzymes play an important role in the removal of potentially toxic lipophilic compounds by forming glucuronides from uridine diphospho-glucuronic acid.63 In the case of AEDs, UGT enzymes play an important role in the metabolism of CBZ, lamotrigine (LTG), oxcarbazepine, and topiramate, among other drugs.64 Some polymorphisms in the genes coding for UGT enzymes have been reported to have an influence on inter-individual variability of the pharmacokinetic parameters of AEDs. For example, differences in LTG plasma levels have been associated with the UGT1A4 L48 V variant65 and differences in VPA plasma levels with the UGT1A3*5 allele.66 A more recent study suggested the association of UGT1A6 552A>C polymorphism with presence of high VPA plasma levels and ADRs induced by this AED, such as ataxia, liver damage, metabolic changes, tremor, hallucinations, pancreatitis, and excessive weight gain.67

Drug transporters

ABCC2 is an efflux transporter from the superfamily of ATP-binding cassette (ABC) transmembrane proteins, which utilise the energy released by ATP hydrolysis to translocate solutes and drugs across cellular membranes.68 Such AEDs as PHT, CBZ, and VPA are substrates of this transporter. Researchers have observed that when ABCC2 is overexpressed at the blood-brain barrier, some patients may present refractory temporal lobe epilepsy. In contrast, some polymorphisms of the ABCC2 gene may result in a decrease in the transporter's efflux function, which leads to greater penetration of the drug into the brain, triggering mainly neurological ADRs (Fig. 1).69-71 A study of Korean patients receiving VPA found that the g.-1774delG polymorphism of the ABCC2 gene was associated with presence of ADRs, with patients carrying the G allele being more likely to experience dizziness, headache, somnolence, diplopia, dysarthria, and tremor than those with the deletion allele (P=.0057). Researchers also found that frequency of the T allele at g.-24C>T (rs717620) was higher in the group of patients with neurological ADRs than in the group of patients without these reactions (P=.0274).71 However, other studies in Korean and Japanese populations found no association between ABCC2 polymorphisms and VPA-related ADRs.72,73

Figure 1.

Participation of the ABCB1 and ABCC2 transporters at the blood-brain barrier (BBB) in the development of adverse reactions to antiepileptic drugs.

(0.21MB).

Another Korean study of patients receiving CBZ demonstrated an association between the ABCC2 c.1249G>A polymorphism and presence of neurological ADRs. Patients with GA or AA genotypes at this locus reported a higher frequency of neurological ADRs (P=.005).74 An earlier report described that ABCC2 g.-1774delG polymorphism and a haplotype containing the g.-1549G>A, g.-24C>T, c.334-49C>T, and c.3972C>T variations are a predisposing factor for developing liver complications associated with several drugs75; however, these have not been studied in AEDs.

P-glycoprotein (Pgp), coded by the ABCB1 gene, is another transporter of the ABC superfamily, and has been widely studied in the context of AED resistance and pharmacokinetic variability of substrate AEDs of human Pgp, such as PHT, phenobarbital, and LTG.76 Although 3 ABCB1 polymorphisms (3435C>T, 2677G>T/A, and 1236C>T) have been associated with variability of PHT plasma levels,77,78 their association with neurotoxic effects remains unclear.50,79

Cutaneous adverse reactions to antiepileptic drugs and their association with alleles of the HLA system

Type B reactions are idiosyncratic, and even though they manifest in a smaller proportion of patients, they result in higher morbidity and mortality rates and require immediate withdrawal of the drug or even an additional treatment to control ADRs.41 These reactions include cutaneous adverse drug reactions (cADR), which have been reported to occur with AEDs and other drug groups. These reactions have an incidence of 10 cases per 1000 new users.80

There are several subtypes of cADRs, with different degrees of severity. Maculopapular exanthema (MPE) is the mildest form, usually involving only the skin and not displaying systemic symptoms; MPE resolves with withdrawal of the drug causing the reaction.81 Drug-induced hypersensitivity syndrome (DIHS) and drug reaction with eosinophilia and systemic symptoms (DRESS) manifest between 3 weeks and 3 months after treatment onset; they are characterised by skin eruption, usually pruritic, by lymphadenopathy, fever of 38-40°C, and reactivation of human herpesvirus 6, which can remain active weeks after the drug is withdrawn.82,83

The most severe forms of cADR are Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with mortality rates of 5% in SJS and 30% in TEN, and a calculated incidence of 2 cases per million population.84,85 Both syndromes are variants of a single condition, but with different percentages of skin detachment (less than 10% in SJS and more than 30% in TEN).86,87 The most important sequelae affect the eyes: up to 75% of patients with TEN may present such severe ophthalmological complications as blindness.88,89

Although the mechanisms causing cADRs are still to be fully defined, 2 theories have been proposed: the hapten/prohapten theory, and the hypothesis of pharmacological interactions between drugs and immune receptors (p-i). In the first case, the drug molecule, being too small to elicit an immune response, acts as a hapten or prohapten; it forms covalents bonds with endogenous proteins, creating a hapten-carrier complex, and becomes immunogenic.90 The hapten-carrier complex is processed by antigen presenting cells in the major histocompatibility complex (MHC) in the lymph nodes and other tissues, which stimulates T cell production and the subsequent clinical manifestations.91 In contrast, the p-i theory (pharmacological interaction of drugs with immune receptors) suggests that some drugs may bind directly and reversibly (non-covalent bond) to immune receptors, such as the MHC or T cell receptor, stimulating T cells specific to the inducing drug.92

In humans, the genetic region of the MHC is known as the human leukocyte antigen system, and comprises a group of highly polymorphic genes located at 6p21.93 The HLA system is conventionally divided into 3 regions known as classes I, II (classic molecule), and III. The most polymorphic exons in the genes of the classic molecule are those coding for the binding sites for peptides of class I and II HLA molecules94 (Fig. 2). Therefore, pharmacogenetic research has focused in recent years on the identification of class I and (to a lesser extent) class II HLA alleles associated with cADRs (Table 4).

Figure 2.

HLA class I and II genes and alleles: organisation of HLA system genes; (above) exons are shown as squares and introns as lines; above the squares are labels indicating the HLA molecule domains (depicted below) coded for by each exon; exons shown in white are those that contain the majority of the polymorphisms included in these genes.

(0.19MB).
Table 4.

HLA alleles associated with cutaneous adverse reactions caused by antiepileptic drugs.a

AED causing cADRs  HLA allele  cADR subtype  Population  P  OR  95% CI  Reference 
CBZ  B*15:02  SJS/TEN  Han Chinese  3.13 E-27  25.04  126-495.22  Chung et al.95 
      Thai  NR  54.43  16.28-181.96  Tangamornsukan et al.99 
      Malaysian  NR  221.00  3.85-12694.65   
  B*15:11  SJS/TEN  Japanese  .0263  9.76  2.01-47.5  Kaniwa et al.103 
  A*31:01  MPE/HSS  Han Chinese  .0021  12.17  3.6-41.2  Hung et al.96 
    SJS/TEN  Northern Europe  8 E-5  25.93  4.93-116.18  McCormack et al.81 
    SJS/TEN/DIHS  Japanese  3.4 E-15  10.8  5.9-19.6  Ozeki et al.105 
  A*02:01  MPE  Han Chinese  .033  NR  NR  Li et al.106 
PHT  B*15:02  SJS/TEN/HSS  Han Chinese  .001  17.6  NA  Man et al.97 
  B*15:02  SJS/TEN  Han Chinese  .0041  5.1  1.8-15.1  Hung et al.107 
  C*08:01  SJS/TEN    .0281  3.0  1.1-7.8   
  B*13:01      .0154  3.7  1.4-10.0   
  DRB1*1602      .0128  4.3  1.4-12.8   
LTG  B*15:02  SJS/TEN/HSS  Han Chinese  .001  17.6  NR  Man et al.97 
  A*30:01  MPE  Han Chinese  .013  NR  NR  Li et al.106 
  B*13:02  MPE    .013  NR  NR   
OXC  B*15:02  SJS/TEN  Han Chinese  8.4 E-4  80.7  3.8-1714.4  Hung et al.107 

CBZ: carbamazepine; DIHS: drug-induced hypersensitivity syndrome; AED: antiepileptic drug; HLA: human leukocyte antigen; HSS: hypersensitivity syndrome; CI: confidence interval; LTG: lamotrigine; MPE: maculopapular exanthema; NR: not reported; OR: odds ratio; OXC: oxcarbazepine; PHT: phenytoin; cADR: cutaneous adverse drug reaction; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis.

a

We included some studies of HLA alleles reported in the literature.

In 2004, Chung et al.95 showed a strong association between the HLA-B*15:02 allele and CBZ-induced SJS in Chinese patients from the province of Han. All patients with SJS (n=44) tested positive for this allele, while only 3% of CBZ-tolerant patients (n=101) and 8.6% of the healthy individuals (n=93) carried the HLA-B*15:02 allele (OR: 2.504, 95% CI, 1.26-49.522, P<.001). This association has been confirmed by other studies in patients from Han province, as well as from central and south-east China,96-98 Malaysia, and Thailand.99 This important finding led the FDA to include this information in the labelling of CBZ packaging and to recommend genetic testing for HLA alleles before starting treatment in patients of Asian descent.100 In contrast, other studies have shown that this allele is not universal and depends upon the study population. Thus, no association was found between the HLA-B*15:02 allele and patients with SJS in white and Japanese populations101,102; however, the frequency of the HLA-B*15:11 allele was reported to be higher in Japanese patients with SJS than in the general population.103

An association has also been reported between the HLA-A*31:01 allele and MPE or hypersensitivity syndrome (HSS) induced by CBZ in Chinese patients from Han province; the allele was found in 25.8% of patients with cADRs and only 2.8% of CBZ-tolerant patients.96 This same allele was found to be associated with CBZ-induced cADRs in patients from northern European countries,81 but no association has been found with cADRs induced by PHT or LTG.104

Similarly, 3 HLA haplotypes associated with AED-induced cADRs have been reported: the 8.1 ancestral haplotype HLA-A*01:01/-Cw*07:01/-B*08:01/-DRB1*03:01/-DQA1*05:01/-DQB1*02:01, associated with CBZ-induced HSS in white populations108; and HLA-A*24:01/-B*59:01/-C*01:02 and HLA-A*02:01/-B*15:18/-C*07:04, with high relative risk values for severe cADRs induced by CBZ in Japanese patients (16.09 and 28.94, respectively).109

The association of genetic variants close to the HLA-E locus (rs1264511) and the motilin (rs2894342) and the CYP2B6 genes (rs1042389) with the presence of CBZ-induced cADRs has also been reported in a Han Chinese population; however, these results were not robust.96

Conclusion

The data reviewed show that interethnic variability has a strong effect on the association of genetic polymorphisms with presence of AED-induced ADRs. To date, research into the HLA-B*15:02 allele and its relationship with CBZ-induced cADRs in patients of Asian birth or descent has been essential in the pharmacogenetic study of ADRs induced by antiepileptics. Therefore, such regulatory agencies as the FDA have considered this allele a pharmacogenetic biomarker for these populations. Nevertheless, there continues to be controversy regarding the replication of results in other populations, including Asian populations.

Another important finding in the pharmacogenetics of AEDs is the association of CYP2C9*2 and *3 alleles with the development of neurological ADRs due to decreased enzymatic activity of CYP2C9. Furthermore, ABCC2 variants are gaining importance in the presence of ADRs since they participate in the transport of AEDs across the blood-brain barrier; however, this association has not been demonstrated sufficiently. Assessing the participation of genes coding for AED receptors, such as SCN1A, SCN2A, and GABRA1, in the appearance of ADRs may also be an interesting line of research.

The identification of pharmacogenetic biomarkers enabling undesired effects of AEDs to be predicted would help increase safety when prescribing these drugs.

Funding

This review article was drafted as part of a project funded by the Consejo Nacional de Ciencia y Tecnología (CONACYT #167261) of Mexico and the doctoral research grant (CONACYT #369708) awarded to Ingrid Fricke-Galindo. This study was coordinated within the Red Iberoamericana de Farmacogenética y Farmacogenómica (SIFF-RIBEF www.ribef.com).

Conflicts of interest

The authors have no conflicts of interest to declare.

References
[1]
M. López-López, J.L. Guerrero-Camacho, I.M. Familiar-López, H. Jung-Cook, T. Corona-Vázquez, M.E. Alonso-Vilatela.
Farmacogenómica: búsqueda de la terapia personalizada.
Rev Neurol, 39 (2004), pp. 1063-1071
[2]
D.M. Roden, A.L.J.T. Gerge.
The genetic basis of variability in drug responses.
Nat Rev Drug Discov, 1 (2002), pp. 37-42
[3]
J. Lazarou, B.H. Pomeranz, P.N. Corey.
Incidence of adverse drug reactions in hospitalized patients.
JAMA, 279 (1998), pp. 1200-1205
[4]
M. Pirmohamed, S. James, S. Meakin, C. Green, A.K. Scott, T.J. Walley, et al.
Adverse drug reactions as cause of admission to hospital: prospective analysis of 18820 patients.
[5]
K. Wester, A.K. Jönsson, O. Spigset, H. Druid, S. Hägg.
Incidence of fatal adverse drug reactions: a population based study.
Br J Clin Pharmacol, 65 (2007), pp. 573-579
[6]
D.S. Budnitz, M.C. Lovegrove, N. Shehab, C.L. Richards.
Emergency hospitalizations for adverse drug events in older Americans.
N Engl J Med, 365 (2011), pp. 2002-2012
[7]
A.L.F. Chan, H.Y. Lee, C.-H. Ho, T.-M. Cham, S.J. Lin.
Cost evaluation of adverse drug reactions in hospitalized patients in Taiwan: a prospective, descriptive, observational study.
Curr Therap Res, 69 (2008), pp. 118-129
[8]
T. Morimoto, T.K. Gandhi, A.C. Seger, T.C. Hsieh, D.W. Bates.
Adverse drug events and medication errors: detection and classification methods.
Qual Saf Health Care, 13 (2004), pp. 306-314
[9]
D.C. Suh, B.S. Woodall, S.K. Shin, E.R. Hermes-De Santis.
Clinical an economic impact of adverse drug reactions in hospitalized patients.
Ann Pharmacother, 34 (2000), pp. 1373-1379
[10]
World Health Organization.
International drug monitoring: the role of national centers Report of a WHO meeting.
World Health Organ Tech Rep Ser, 498 (1972), pp. 1-25
[11]
I.R. Edwards, J.K. Aronson.
Adverse drug reactions: definitions, diagnosis, and management.
Lancet, 356 (2000), pp. 1255-1259
[12]
S. Scott, J. Thompson.
Adverse drug reactions.
Anaesth Intensive Care, 12 (2011), pp. 319-323
[13]
P. Perucca, F.G. Gilliam.
Adverse effects of antiepileptic drugs.
Lancet Neurol, 11 (2012), pp. 792-802
[14]
E. Bruno, A. Bartoloni, L. Zammarchi, M. Strohmeyer, F. Bartalesi, J.A. Bustos, et al.
Epilepsy and neurocysticercosis in Latin America: a systematic review and meta-analysis.
PLoS Negl Trop Dis, 7 (2013), pp. e2480
[15]
A.K. Ngugi, C. Bottomley, I. Kleinschmidt, J.W. Sander, C.R. Newton.
Estimation of the burden of active and life-time epilepsy: a meta-analytic approach.
[16]
R.N. Brogden, R.C. Heel, T.M. Speight, G.S. Avery.
Clobazam. A review of its pharmacological properties and therapeutic use in anxiety.
Drugs, 20 (1980), pp. 161-178
[17]
R.S. Greenwood.
Adverse effects of antiepileptic drugs.
Epilepsia, 41 (2000), pp. S42-S52
[18]
J.L. Herranz, J.A. Armijo, R. Arteaga.
Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children.
Epilepsia, 29 (1988), pp. 794-804
[19]
D.S. Hill, B.J. Wlodarczyk, A.M. Palacios, R.H. Finnell.
Teratogenic effects of antiepileptic drugs.
Expert Rev Neurother, 10 (2010), pp. 943-959
[20]
N. Jarernsiripornkul, P. Senacom, V. Uchaipichat, N. Chaipichit, J. Krska.
Patient reporting of suspected adverse drug reactions to antiepileptic drugs: factors affecting attribution accuracy.
Epilepsy Behav, 24 (2012), pp. 102-106
[21]
T.A. Ketter, R.M. Post, W.H. Theodore.
Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders.
Neurology, 53 (1999), pp. S53-S67
[22]
A. Massot, R. Vivanco, A. Principe, J. Roquer, R. Rocamora.
Post-authorisation study of eslicarbazepine as treatment for drug-resistant epilepsy: preliminary results.
Neurología, 29 (2014), pp. 94-101
[23]
J.M. Pellock.
Carbamazepine side effects in children and adults.
Epilepsia, 28 (1987), pp. S64-S70
[24]
E.B. Posner, K. Mohamed, A.G. Marson.
A systematic review of treatment of typical absence seizures in children and adolescents with ethosuximide, sodium valproate or lamotrigine.
[25]
T. Tomson, D. Battino.
Efectos teratogénicos de fármacos antiepilépticos.
Neurol Arg, 5 (2013), pp. 49-53
[26]
M. Riverol, A. Gómez-Ibáñez, M. Carmona-Iragui.
Avances en el tratamiento de la epilepsia.
Medicine, 10 (2009), pp. 3091-3099
[27]
G. Zaccara, P.F. Gangemi, M. Cincotta.
Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies.
[28]
G. Zaccara, P. Gangemi, P. Perucca, L. Specchio.
The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials.
[29]
G. Zaccara, F. Giovannellia, M. Cincotta, A. Verrotti, E. Grillo.
The adverse event profile of perampanel: meta-analysis of randomized controlled trials.
Eur J Neurol, 20 (2013), pp. 1204-1211
[30]
G. Zaccara, F. Giovannelli, D. Maratea, V. Fadda, A. Verrotti.
Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine.
[31]
G. Zaccara, P. Perucca, G. Loiacono, F. Giovannelli, A. Verrotti.
The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials.
Epilepsia, 54 (2013), pp. 66-74
[32]
P. Perucca, J. Carter, V. Vahe, F.G. Gilliam.
Adverse antiepileptic drug effects. Toward a clinically and neurobiologically relevant taxonomy.
[33]
J.A. Cramer, R. Fisher, E. Ben-Menachem, J. French, R.H. Mattson.
New antiepileptic drugs: comparison of key clinical trials.
Epilepsia, 40 (1999), pp. 590-600
[34]
P. Kwan, M.J. Brodie.
Early identification of refractory epilepsy.
N Engl J Med, 342 (2000), pp. 314-319
[35]
F. Gilliam, J. Carter, V. Vahle.
Tolerability of antiseizure medications. Implications for health outcomes.
Neurology, 63 (2004), pp. S9-S12
[36]
R.J. De Kinderen, S.M. Evers, R. Rinkens, D. Postulart, C.I. Vader, M.H. Majoie, et al.
Side-effects of antiepileptic drugs: the economic burden.
[37]
Madian AG, Baker Jones R. Variable drug response: genetic evaluation. In: Cooper DN, editor. Encyclopedia of life sciences (eLS). Genetics & Disease. Chichester: John Wiley & Sons Ltd; 2013. Available from: http://www.els.nethttp://dx.doi.org/10.1002/9780470015902.a0006001.pub2
[38]
W.E. Evans, H.L. McLeod.
Pharmacogenomics-drug disposition, drug targets and side effects.
N Engl J Med, 348 (2003), pp. 538-549
[39]
W. Kalow, B.K. Tang, I. Endrenyi.
Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research.
Pharmacogenetics, 8 (1998), pp. 283-289
[40]
R. Weisenhilboum.
Inheritance and drug response.
N Engl J Med, 348 (2003), pp. 529-537
[41]
G. Zaccara, D. Franciotta, E. Perucca.
Idiosyncratic adverse reactions to antiepielptic drugs.
Epilepsia, 48 (2007), pp. 1223-1244
[42]
G.D. Anderson.
Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs.
Neurology, 63 (2004), pp. S3-S8
[43]
A. Llerena, P. Dorado, F. O’Kirwan, R. Jepson, J. Licinio, M.L. Wong.
Lower frequency of CYP2 C9*2 in Mexican-Americans compared to Spaniards.
Pharmacogenomics J, 4 (2004), pp. 403-406
[44]
T.H. Sullivan-Klose, B.I. Ghanayem, D.A. Bell, Z.Y. Zhang, L.S. Kaminsky, G.M. Shenfield, et al.
The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism.
Pharmacogenetics, 6 (1996), pp. 341-349
[45]
P. Dorado, M.G. Sosa-Macías, E.M. Peñas-Lledó, R.E. Alanis-Bañuelos, M.L. Wong, J. Licinio, et al.
CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards.
Pharmacogenomics J, 11 (2011), pp. 108-112
[46]
M. Sosa-Macías, B.P. Lazalde-Ramos, C. Galaviz-Hernández, H. Rangel-Villalobos, J. Salazar-Flores, V.M. Martínez-Sevilla, et al.
Influence of admixture components on CYP2C9*2 allele frequency in eight indigenous populations from Northwest Mexico.
Pharmacogenomics J, 13 (2013), pp. 567-572
[47]
L.J. Dickmann, A.E. Rettie, M.B. Kneller, R.B. Kim, A.J. Wood, C.M. Stein, et al.
Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans.
Mol Pharmacol, 60 (2001), pp. 382-387
[48]
R.S. Kidd, T.B. Curry, S. Gallagher, T. Edeki, J. Blaisdell, J.A. Goldstein.
Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin.
Pharmacogenetics, 11 (2001), pp. 803-808
[49]
C. Depondt, P. Godard, R.S. Espel, A.L. da Cruz, P. Lienard, M. Pandolfo.
A candidate gene study of antiepileptic drug tolerability and efficacy identifies an association of CYP2C9 variants with phenytoin toxicity.
Eur J Neurol, 18 (2011), pp. 1159-1164
[50]
P. Dorado, E. López-Torres, E.M. Peñas-Lledó, J. Martínez-Antón, A. Llerena.
Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9 CYP2 C19 and ABCB1 genetic polymorphisms.
Pharmacogenomics J, 13 (2013), pp. 359-361
[51]
K. Babu, V. Ramesh, A. Samidorai.
Charles C Cytochrome P450 2C9 gene polymorphism in phenytoin induced gingival enlargement: a case report.
J Pharm Bioallied Sci, 5 (2013), pp. 237-239
[52]
H. Ninomiya, K. Mamiya, S-I. Matsuo, I. Ieiri, S. Higuchi, N. Tashiro.
Genetic polymorphism of the CYP2 C subfamily and excessive serum phenytoin concentration with central nervous system intoxication.
Ther Drug Monit, 22 (2000), pp. 230-232
[53]
K. Ramasamy, S.K. Narayan, S. Chanolean, A. Chandrasekaran.
Severe phenytoin toxicity in a CYP2 C9*3*3 homozygous mutant from India.
Neurol India, 55 (2007), pp. 408-409
[54]
Pharmgkb Dutch Pharmacogenetics working group guideline for phenytoin and CYP2C9 (2011). Available from: http://www.pharmgkb.org/guideline/PA166104984 [accessed 07.06.14].
[55]
J.A. Goldstein.
Clinical relevance of genetic polymorphisms in the human CYP2 C subfamily.
Br J Clin Pharmacol, 52 (2001), pp. 349-355
[56]
K. Mamiya, I. Ieiri, J. Shimamoto, W. Yukawa, J. Imai, H. Ninomiya, et al.
The effects of genetic polymorphisms of CYP2C9 and CYP2 C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics.
Epilepsia, 39 (1998), pp. 1317-1323
[57]
C.F. Thorn, M. Whirl-Carrillo, J.S. Leeder, T.E. Klein, R.B. Altman.
PharmGKB summary: phenytoin pathway.
Pharmacogenet Genomics, 22 (2012), pp. 466-470
[58]
P.A. Dennery.
Effects of oxidative stress on embryonic development.
Birth Defect Res C Embryo Today, 81 (2007), pp. 155-162
[59]
E.M. Azzato, R.A. Chen, S. Wacholder, S.J. Chanock, M.A. Klebanoff, N.E. Caporaso.
Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations.
Pharmacogenet Genomics, 20 (2010), pp. 58-63
[60]
M.P. Kalapos.
Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation.
Adverse Drug React Toxicol Rev, 21 (2002), pp. 123-141
[61]
K. Ueda, T. Ishitsu, T. Seo, N. Ueda, T. Murata, M. Hori, et al.
Glutathione S-transferase M1 null genotype as a risk factor for carbamazepine-induced mild hepatotoxicity.
Pharmacogenomics, 8 (2007), pp. 435-442
[62]
Y. Fukushima, S. Takayuli, N. Hashimoto, Y. Higa, T. Ishitsu, K. Nakagawa.
Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum γ-glutamyltransferase in valproic acid-treated patients.
Clin Chim Acta, 389 (2008), pp. 98-102
[63]
C. Guillemette.
Pharmacogenomics of human UDP glucuronosyltransferase enzymes.
Pharmacogenomics J, 3 (2003), pp. 136-158
[64]
J. Saruwatari, T. Ishitsu, K. Nakagawa.
Update on the genetic polymorphisms of drug-metabolizing enzymes in antiepileptic drug therapy.
Pharmaceuticals, 3 (2010), pp. 2709-2732
[65]
M.I. Gulcebi, A. Ozkaynakcı, M.Z. Goren, R.G. Aker, C. Ozkara, F.Y. Onat.
The relationship between UGT1 A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy.
[66]
X.M. Chu, L.F. Zhang, G.J. Wang, S.N. Zhang, J.H. Zhou, H.P. Hao.
Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients.
Eur J Clin Pharmacol, 68 (2012), pp. 1395-1401
[67]
M. Munisamy, M. Tripathi, M. Behari, S. Raghavan, D.C. Jain, B. Ramanujam, et al.
The effect of uridine diphosphate glucuronosyltransferase (UGT)1 A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: a pharmacogenetic approach.
Mol Diagn Ther, 17 (2013), pp. 319-326
[68]
P.M. Jones, A.M. George.
The ABC transporter structure and mechanism: perspectives on recent research.
Cell Mol Life Sci, 61 (2004), pp. 682-699
[69]
S.M. Dombrowski, S.Y. Desai, M. Marroni, L. Cucullo, K. Goodrich, W. Bingaman, et al.
Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy.
Epilepsia, 42 (2001), pp. 1501-1506
[70]
H. Potschka, M. Fedrowitz, W. Löscher.
Multidrug resistance protein MRP2 contributes to blood–brain barrier function and restricts antiepileptic drug activity.
J Pharmacol Exp Ther, 306 (2003), pp. 124-131
[71]
J.H. Yi, Y.-J. Cho, W.-J. Kim, M.G. Lee, J.H. Lee.
Genetic variations of ABCC2 gene associated with adverse drug reactions to valproic acid in Korean epileptic patients.
Genomics Inform, 11 (2013), pp. 254-262
[72]
D.W. Kim, S.K. Lee, K. Chu, I.J. Jang, K.S. Yu, J.Y. Cho, et al.
Lack of association between ABCB1, ABCG2 and ABCC2 genetic polymorphisms and multidrug resistance in partial epilepsy.
Epilepsy Res, 84 (2009), pp. 86-90
[73]
T. Seo, T. Ishitsu, K. Oniki, T. Abe, T. Shuto, K. Nakagawa.
ABCC2 haplotype is not associated with drug-resistant epilepsy.
J Pharm Pharmacol, 60 (2008), pp. 631-635
[74]
W.J. Kim, J.H. Lee, J. Yi, Y.-J. Cho, K. Heo, S.H. Lee, et al.
A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy.
Pharmacogenet Genomics, 20 (2010), pp. 249-256
[75]
J.H. Choi, B.M. Ahn, J. Yi, J.H. Lee, J.H. Lee, S.W. Nam, et al.
MRP2 haplotypes confer differential susceptibility to toxic liver injury.
Pharmacogenet Genomics, 17 (2007), pp. 403-415
[76]
C. Luna-Tortós, M. Fedrowitz, W. Löscher.
Several major antiepileptic drugs are substrates for human P-glycoprotein.
Neuropharmacology, 55 (2008), pp. 1364-1375
[77]
S. Hoffmeyer, O. Burk, O. von Richter, H.P. Arnold, J. Brockmoller, A. Johne, et al.
Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
Proc Natl Acad Sci U S A, 97 (2000), pp. 3473-3478
[78]
C.C. Hung, C.C. Chen, C.J. Lin, H.H. Liou.
Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs.
Pharmacogenet Genomics, 18 (2008), pp. 390-402
[79]
C.E. Szoeke, M. Newton, J.M. Wood, D. Goldstein, S.F. Berkovic, T.J. O’Brien, et al.
Update on pharmacogenetics in epilepsy: a brief review.
Lancet Neurol, 5 (2006), pp. 189-196
[80]
R. Stern.
Exanthematous drug eruptions.
N Engl J Med, 366 (2012), pp. 2492-2501
[81]
B.A. McCormack, A. Alfiveric, S. Bourgeois, J.J. Farrell, D. Kasperavičiūtė, M. Carrington, et al.
HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.
N Engl J Med, 364 (2011), pp. 1134
43
[82]
M. Eshki, L. Allanore, P. Musette, B. Milpied, A. Grange, J.-C. Guillaume, et al.
Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms. A cause of unpredictable multiorgan failure.
Arch Dermatol, 145 (2009), pp. 67-72
[83]
T. Shiohara, M. Inaoka, Y. Kano.
Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses.
Allergol Int, 55 (2006), pp. 1-8
[84]
M. Aihara.
Pharmacogenetics of cutaneous adverse drug reactions.
J Dermatol, 38 (2011), pp. 246-254
[85]
B. Rzany, M. Mockenhaupt, S. Baur, W. Schröder, S. Ulrich, J. Mueller, et al.
Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): structure and results of a population-based registry.
J Clin Epidemol, 49 (1996), pp. 769-773
[86]
S. Bastuji-Garin, B. Rzany, R.S. Stern, N.H. Shear, L. Naldi, J.C. Roujeau.
Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.
Arch Dermatol, 129 (1993), pp. 92-96
[87]
J.C. Roujeau.
Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme.
J Dermatol, 24 (1997), pp. 726-729
[88]
S. Goyal, P. Gupta, C.M. Ryan, M. Kazlas, N. Noviski, R.L. Sheridan.
Toxic epidermal necrolysis in children: medical surgical, and ophthalmologic considerations.
J Burn Care Res, 30 (2009), pp. 437-449
[89]
S. Magina, C. Lisboa, V. Leal, J. Palmares, J. Mesquita-Guimarães.
Dermatological and ophthalmological sequels in toxic epidermal necrolysis.
Dermatology, 207 (2003), pp. 33-36
[90]
B. Schnyder, W.J. Pichler.
Mechanisms of drug-induced allergy.
Mayo Clin Proc, 84 (2009), pp. 268-272
[91]
D.J. Naisbitt, S.F. Gordon, M. Prirmohamed, B.K. Park.
Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment.
Drug Saf, 23 (2000), pp. 483-507
[92]
W.J. Pichler, A. Beeler, M. Keller, M. Lerch, S. Posadas, D. Schmid, et al.
Pharmacological interaction of drugs with immune receptors: the p-i concept.
Allergol Int, 55 (2006), pp. 17-25
[93]
R. Barquera, J. Zúñiga, R. Hernández-Díaz, V. Acuña-Alonzo, K. Montoya-Gama.
HLA class I and class II haplotypes in admixed families from several regions of Mexico.
Mol Immunol, 45 (2008), pp. 1171-1178
[94]
J. Granados-Arriola, C. Álvarez-Carreño, A. Lara-Mejía, M.A. Reyes-Servín, L.F. Valdés-Corona.
Inmunogenética del complejo principal de histocompatibilidad.
Genética clínica, pp. 445-460
[95]
W.H. Chung, S.I. Hung, H.S. Hong, M.S. Hsih, L-C. Yang, H-C. Ho, et al.
Medical genetics: a marker for Stevens-Johnson syndrome.
Nature, 428 (2004), pp. 486
[96]
S.I. Hung, W.H. Chung, S.H. Jee, W.C. Chen, Y.T. Chang, W.-R. Lee, et al.
Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.
Pharmacogenet Genom, 16 (2006), pp. 297-306
[97]
C. Man, P. Kwan, L. Baum, E. Yu, K.M. Lau, A. Cheng, et al.
Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese.
Epilepsia, 48 (2007), pp. 1015-1018
[98]
X.Q. Wang, X.B. Shi, R. Au, F.S. Chen, F. Wang, S.Y. Lang.
Influence of chemical structure on skin reactions induced by antiepileptic drugs—the role of the aromatic ring.
Epilepsy Res, 94 (2011), pp. 213-217
[99]
W. Tangamornsukan, N. Chaiyakunapruk, S. Ratchadaporn, M. Lohitnavy, W. Tassaneeyakul.
Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.
JAMA Dermatol, 149 (2013), pp. 1025-1032
[100]
Carbamazepine (marketed as carbatrol, equetro, tegreto and generics) FDA, US Food and Drug Administration. 2007. Available from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150841.htm.
[101]
C. Lonjou, L. Thomas, N. Borot, N. Ledger, C. de Toma, H. LeLouet, et al.
A marker for Stevens-Johnson syndrome…: ethnicity matters.
Pharmacogenomics J, 6 (2006), pp. 265-268
[102]
M. Ueta, K. Tokunaga, C. Sotozon, T. Inatomi, T. Yabe, M. Matsushita, et al.
HLA class i and ii gene polymorphisms in Stevens-Johnson syndrome with ocular complications in Japanese.
Mol Vis, 14 (2008), pp. 550-555
[103]
N. Kaniwa, Y. Saito, M. Ahijara, K. Matsunaga, M. Tohkin, K. Kurose, et al.
HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in japanese patients.
Epilepsia, 51 (2010), pp. 2461-2465
[104]
M. McCormack, T.J. Urban, K.V. Shianna, N. Walley, M. Pandolfo, C. Depondt, et al.
Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.
Pharmacogenomics, 13 (2012), pp. 399-405
[105]
T. Ozeki, T. Mushiroda, A. Yowang, A. Takahashi, M. Kubo, Y. Shirakata, et al.
Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population.
Hum Mol Genet, 20 (2011), pp. 1034-1041
[106]
L.J. Li, F.Y. Hu, X.T. Wu, D.M. And, B. Yan, D. Zhoy.
Predictive markers for carbamazepine and lamotrigine-induced maculopapular exanthema in Han Chinese.
Epilepsy Res, 106 (2013), pp. 296-300
[107]
S.I. Hung, W.H. Chung, Z.S. Liu, S.H. Chen, M.S. Hsih, R.C. Hui, et al.
Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese.
Pharmacogenomics, 11 (2010), pp. 349-356
[108]
M. Pirmohamed, K. Lin, D. Chadwick, B.K. Park.
TNFalpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients.
Neurology, 56 (2001), pp. 890-896
[109]
H. Ikeda, Y. Takahashi, E. Yamazaki, T. Fujiwara, N. Kaniwa, Y. Saito, et al.
HLA Class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions.

Please cite this article as: Fricke-Galindo I, Jung-Cook H, LLerena A, López-López M. Farmacogenética de reacciones adversas a fármacos antiepilépticos. Neurología. 2018;33:165–176.

Copyright © 2014. Sociedad Española de Neurología
Descargar PDF
Opciones de artículo
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos