The influence of genetic variant on response to ASMs

Pharmacogenomics, i.e., the influence of genetic variants on drug response or adverse effects, bear the potential to support the choice of the most suitable ASMs. Genes can affect drug response influencing pharmacokinetic parameters by causing variable activity of the systems responsible for the metabolism and transport of the drug as well as influencing pharmacodynamics through drug targets.Genetic influence on ASMs pharmacokinetics is primarily related to the polymorphism of enzymes involved in ASMs metabolism. CYP۲C۹/۲C۱۹ polymorphisms may be relevant in the metabolism/bioavailability of phenytoin, brivaracetam, CLB and partially valproate, as well as barbiturates, while UGT (UGT۱A۴ and UGT۲B۷) variants are associated with variable kinetics of lamotrigine and valproate.Progress in genomic testing has resulted in identification of a large number of epileptic genes, which account for a large proportion of nonacquired epilepsies. Upon identifying the genetic basis of the disease, the treatment can be directed toward correction of specific metabolic defects such as conduction of ketogenic diet for glucose transporter-۱ deficiency or pyridoxine use for pyridoxine-dependent epilepsies. Knowing the genetic basis of the disease can help in avoiding ASMs that can aggravate the pathogenic defect, such as sodium channel-blocking drugs in Dravet syndrome caused by mutation in SCN۱A. However, in the treatment of early-onset epileptic encephalopathy due to glutamate ionotropic receptor NMDA-type subunit ۲A (GRIN۲A) missense mutation (L۸۱۲M), memantine administration resulted in decreased seizure frequency.No reliable gene marker of resistance to ASMs has been identified to date, although there are data suggesting the possible role of ABCB۱ and ABCC۲ gene variants. By analyzing several HLA alleles, we can identify high-risk individuals for development of SJS and TEN induced by CBZ, most important of which are HLAB* ۱۵:۰۲ and HLAA*۳۱:۰۱. Also, variant allele carriers have an increased risk in case of the use of OXC, phenytoin and lamotrigine.