Review of pharmacogenetics of antiseizure medications: focusing on genetic variants of mechanistic targets

Abstract

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs.

Keywords: antiseizure medication; drug-resistant epilepsy; genetic variants; mechanistic targets; pharmacogenetic studies.

FIGURE 1

Coding Variants’ Impact on Antiseizure Medication. The schematic illustrates the impact of coding variants on the target, transportation, and metabolism of antiseizure medication (ASM). Typically, following oral administration of ASMs, the drug undergoes absorption in the gut, metabolism in the liver, and passage across the blood-brain barrier to reach its mechanistic target and exert its therapeutic effect. Genetic variants of efflux transporters in the gut, such as glycoprotein-P, can actively pump the drug back into the intestinal lumen, reducing its absorption. Similarly, variants of glycoprotein-P at the blood-brain barrier may facilitate the drug’s return to the bloodstream, decreasing its concentration in the brain. Genetic variants can also induce changes in metabolizing enzymes, such as cytochrome P450, in the liver. This can affect the rate of drug metabolism, leading to variable concentrations in the blood, differences in excretion, and variations in availability at its target site. Consequently, this may alter the effectiveness of ASMs. Additionally, genetic variants within the brain may modify neuronal receptors, compromising ASM’s ability to bind effectively and consequently diminishing its efficacy. *The figures were created with BioRender.com.

FIGURE 2

Impact of Non-Coding Genetic Variants on Antiseizure Medication Response. Genetic variants in non-coding regions, particularly introns, have the potential to disrupt typical splicing patterns. This disruption can lead to changes in protein expression levels and alter receptor functionality, consequently influencing responses to ASMs. The example provided in this Figure 2 focuses on SCN1A rs3812718. (A) The typical expression of SCN1A includes exon 5A and 5N. While 5N is more sensitive to sodium channel-blocking ASMs. (B) Conversely, within SCN1A carrying the rs3812718 variant, the expression of exon 5N is diminished, consequently reducing the abundance of receptors with heightened sensitivity to sodium channel-blocking ASMs. This decrease in receptors results in fewer channels being blocked, ultimately diminishing the antiseizure efficacy. (The ratio of 5A to 5N depicted in the figure does not accurately reflect the true conditions.). *The figures were created with BioRender.com.