Genetic Determinants in HLA and Cytochrome P450 Genes in the Risk of Aromatic Antiepileptic-Induced Severe Cutaneous Adverse Reactions

Abstract

Adverse drug reaction (ADR) is a pressing health problem, and one of the main reasons for treatment failure with antiepileptic drugs. This has become apparent in the event of severe cutaneous adverse reactions (SCARs), which can be life-threatening. In this review, four hypotheses were identified to describe how the immune system is triggered in the development of SCARs, which predominantly involve the human leukocyte antigen (HLA) proteins. Several genetic variations in HLA genes have been shown to be strongly associated with the susceptibility to developing SCARs when prescribed carbamazepine or phenytoin. These genetic variations were also shown to be prevalent in certain populations. Apart from the HLA genes, other genes proposed to affect the risk of SCARs are genes encoding for CYP450 drug-metabolising enzymes, which are involved in the pharmacokinetics of offending drugs. Genetic variants in CYP2C9 and CYPC19 enzymes were also suggested to modulate the risk of SCARs in some populations. This review summarizes the literature on the manifestation and aetiology of antiepileptic-induced SCARs, updates on pharmacogenetic markers associated with this reaction and the implementation of pre-emptive testing as a preventive strategy for SCARs.

Trends of anti-seizure medication prescribing pattern in traumatic brain injury patients for the prevention of posttraumatic seizure in Taiwan

“…From 1996 to 2016 in Taiwan, there were 82 (9 %) cases of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and 38 (13 %) cases of drug reaction with eosinophilia and systemic symptoms (DRESS) related to phenytoin. Although it is suggested to identify individuals at risk of severe side effects based on the pharmacogenetic test, in Taiwan, it is not common clinical practice to start the pharmacogenetic test before initiating phenytoin [24] . As a result, cautious prescribing of phenytoin is advised, weighing the overall benefits against potential complications.…”

Implementation of HLA-B*15:02 Genotyping as Standard-of-Care for Reducing Carbamazepine/Oxcarbazepine Induced Cutaneous Adverse Drug Reactions in Thailand

“…Commonly, the HLA-B*15:02 allele has been reported to be specifically associated with CBZinduced SJS/TEN in Asian populations, and no associations have been reported for drug-induced MPE and DRESS (phenotype-specific biomarker) (Sukasem et al, 2021b). In contrast, HLA-A*31:01 was reported to be associated with CBZ-induced DRESS and MPE (Mockenhaupt et al, 2019;Ahmed et al, 2021). US-FDA recommended that HLA-B*15:02 and HLA-A*31:01 genotypes should be detected to stratify the high risk patients prior CBZ prescription.…”

Pharmacogenetics to Avoid Adverse Drug Reactions

“…Two works are presented in this Issue on antiepileptic drugs. Ahmed et al, reviewed the role of DNA variants in HLA and cytochrome P450 genes in the risk of aromatic antiepilepticinduced severe cutaneous adverse reactions [8]. They summarized the knowledge on HLA, CYP2C9, and CYP2C19, and its role in severe cutaneous adverse reactions, as well as drugs inducing this adverse reaction, such as carbamazepine, phenytoin, lamotrigine, or phenobarbital.…”