Genetic polymorphisms of drug-metabolizing enzymes in older and newer anti-seizure medications

KEYWORDS:

• ASMs
• epilepsy
• metabolism
• pharmacokinetic
• pharmacogenomic
• treatment

1. Introduction

In the early 2000s, research into the genetic polymorphisms of drug-metabolizing enzymes associated with antiseizure medications (ASMs) was viewed as highly promising [1]. The recent introduction of new ASMs on the market prompts the inquiry into the eventual relevance of studying genetic polymorphisms of ASM-metabolizing enzymes within the scientific community, and the extent of evidence supporting their investigation for the management of new ASMs.

2. What is known

Older generation ASMs such as phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), and phenobarbital are known for their narrow therapeutic range and substantial inter-individual variability in pharmacokinetics, as documented in several studies. This variability poses challenges in achieving optimal dosing for individuals. In contrast, second-generation ASMs like levetiracetam seemed to offer a more consistent pharmacokinetic profile, contributing to more predictable treatment outcomes [2].

The metabolism of ASMs primarily occurs via hepatic pathways, where the inter-individual capacity of hepatic metabolism plays a significant role in determining both pharmacokinetic and pharmacodynamic responses. Such metabolic pathway involves various enzymes belonging to the cytochrome P450 family, among which CYP2C9 and CYP2C19 are noteworthy. Genetic polymorphisms in CYP450 enzymes, particularly CYP2C9 and CYP2C19, have been implicated in altering ASM metabolism, as evidenced by population studies [3]. Individuals could be classified into different metabolic phenotypes based on their genetic makeup regarding such enzymes. Identifiable phenotypes include homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs), each of which may require different therapeutic strategies. Such classifications could offer important insights into individualized dosing strategies to optimize therapeutic outcomes. For instance, a reduction of 25% and 50% respectively from the initial dose is suggested in the case of PHT for those who are IM and PM respectively [4].

Nonetheless, the role of CYP3A4, another pivotal liver enzyme involved in ASMs metabolism, should not be overlooked. It is noteworthy that while CYP2C9 and CYP2C19 enzymes show considerable inter-individual variability, CYP3A4 expression on the other hand remains relatively consistent across individuals [5]. CYP3A4 is primarily involved in the metabolism of ASMs such as CBZ, clonazepam, and ethosuximide.

Additionally, alternative metabolic pathways for ASMs involve the microsomal epoxide hydrolase (mEH), encoded by EPHX1 gene. mEH plays a crucial role in the metabolism of reactive xenobiotic epoxides generated by CYP enzymes. Genetic variations in EPHX1 can significantly influence mEH activity. It has been shown that plasma levels of CBZ-10,11-trans-diol increased in carriers of the Try113His haplotype, whereas the opposite occurred in carriers of the His139Arg haplotype, with an elevation in CBZ-10,11-epoxide plasma concentrations [6].

Glucuronidation reactions, promoted by UDP-glucuronosyltransferase (UGT), represent another important pathway in ASM metabolism, contributing to up to 35% of drugs metabolized in phase II reactions [2]. ASMs such as lamotrigine (LTG) and oxcarbazepine (OXC) undergo glucuronidation reactions as part of their metabolic pathways, forming LTG-2-N-glucuronide and 10-monohydroxyderivative, respectively. Several researchers have explored the impact of single nucleotide polymorphisms (SNPs) in UGT genes on the metabolism of such medications. Interestingly, the findings suggested that carriers of the UGT2B7 802T>C variant may necessitate higher OXC doses for effective treatment [7]. Furthermore, distinct studies have underscored elevated LTG concentrations and enhanced clinical outcomes among individuals harboring polymorphisms in UGT1A4, UGT2B7, and UGT2B15 genes [8].

3. What is new

Brivaracetam (BRV) primarily undergoes metabolism via amidase and to, a lesser extent, by CYP2C19, resulting in the formation of two pharmacologically inactive metabolites. The Food and Drug and Administration suggests that patients who are CYP2C19 PM (*2/*2, *2/*3, or * 3/*3) might require dose reductions as they could be at an increased risk of adverse events (AEs). This recommendation may be particularly relevant for the Asian population, where the incidence of CYP2C19 PM is notably higher. However, recent findings from a pharmacokinetic model developed by Yang et al. suggest minimal disparities in plasma exposure across different phenotype populations, indicating that these differences may be unlikely clinically significant [9] (Table 1).

Table 1. Selected studies on genetic polymorphisms of drug-metabolizing enzymes of third generation antiseizure medications.

Antiseizure medication	CytochromeP450 involved in drug-metabolism	Polymorphisms’ influence	Reference
Brivaracetam	CYP2C19*	PM have higher plasma levels (possibly not clinically significant)	Yang et al. [9]
Cannabidiol	CYP2C19*	No difference	Beers et al. [10]
Lacosamide	CYP2C19	PM and IM have higher plasma levels (at risk for AEs)	Ahn et al. [12]
Perampanel	CYP3A4	CYP3A4*1 G have minimal plasma variations CYP3A5 × 3/3 have higher plasma levels than CYP3A51/*3	Okkubo et al. [13] Wang et al. [14]
Stiripentol (in combination with valproic acid)	CYP2C19	CYP2C19 EM have higher VPA plasma levels than CYP2C19 PM	Jogamoto et al. [15]

Legend: AEs adverse events, IM intermediate-metabolizer, PM poor-metabolizer, VPA valproic acid.

*The drug proportion metabolized by this enzyme is limited.

Cannabidiol (CBD) goes through biotransformation mediated by CYP2C9, CYP2C19, and CYP3A4 enzymes. Specifically, the major pharmacologically active metabolite, 7-hydroxy-CBD (7-OH-CBD), is primarily formed via oxidation by CYP2C19, with some contribution from CYP2C9, as demonstrated by Beers et al. The authors described how the formation of 7-OH-CBD was dependent on CYP2C19 activity in liver microsomes, with a significant contribution from CYP2C9. CYP3A4, on the other hand, was responsible for other metabolic pathways unrelated to 7-hydroxylation.

Interestingly, the production of 7-OH-CBD was not associated with different CYP2C19 genotypes [10]. The potential influence of polymorphisms in CYP3A4 and CYP2C9 was not evaluated by the authors and, to our knowledge, is not reported in the literature.

Lacosamide (LCM) is inactivated by the enzymes CYP2C19, CYP2C9, and CYP3A4. Among these, the role of CYP2C19 has been extensively investigated. According to the FDA drug label for LCM, individuals who are CYP2C19 PM exhibit lower concentrations of the inactive O-desmethyl metabolite in their plasma and urine compared to EM. However, LCM plasma concentrations were found to be similar between PMs (n = 4) and EMs (n = 8) [11].

A recent study on 115 patients taking LCM at the same dosage for 1 month showed that the CD ratios in IMs and PMs were 13% and 39% higher, respectively than those in EMs. It is interesting to note that in the same cohort, patients with therapeutic failure had significantly lower levels, while those experiencing AEs had higher LCM levels [12].

Perampanel (PER) is mostly metabolized by the enzyme CYP3A4. Okkubo et al. devised a high-performance liquid chromatography method to explore the relationship between perampanel plasma levels and the CYP3A4*1 G polymorphism in 12 Japanese patients. Despite the study’s small sample size, a minor influence of the CYP3A4*1 G polymorphism on individual variations in perampanel plasma concentrations was observed [13].

In a recent study by Wang et al., involving 135 Chinese pediatric patients administered with PER, it was noted that the concentration-to-dose (CD) ratio increased by 21.5% in patients carrying the CYP3A5 × 3/3 genotype compared to those expressing CYP3A51/*3 [14]. These findings necessitate additional confirmation in future research endeavors.

Stiripentol (STP) is included in the medical arsenal for managing epilepsy associated with Dravet syndrome and is frequently employed in combination with clobazam (CLB) and VPA. STP is a potent inhibitor of CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Consequently, through enzymatic inhibition, it is well known to elevate the concentrations of CLB, N-desmethyl-CLB, and VPA.

The effect of CYP2C9 and CYP2C19 polymorphisms was studied by Jogamoto et al. The authors concluded that when VPA and STP were combined, a significant increase in the VPA CD ratio was observed in patients who were CYP2C19 EM compared to those who were CYP2C19 PM [15].

No literature was found regarding the effects of polymorphisms of drug-metabolizing enzymes on the pharmacokinetics of other third-generation ASMs such as Cenobamate, Eslicarbazepine, Fenfluramine, Pregabalin and Rufinamide. Further studies are encouraging to reduce this gap.

4. Expert opinion

In the era of precision therapy, pharmacogenomics plays an attractive role in tailoring epilepsy treatment. By integrating pharmacogenomic insights into clinical practice, clinicians may be able to identify the most suitable drug and dosage regimen for each patient, minimizing the need for therapeutic drug monitoring. Moreover, the development of drug-resistant epilepsy (currently defined as failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules) could be prevented and optimized clinical outcomes might be achieved. However, it remains crucial to recognize the modest clinical influence of genetic variations, particularly involving enzymes like CYP2C9 and CYP2C19, on ASM treatment efficacy.

Indeed, while these enzymes play significant roles in ASM metabolism, their influence on treatment response appears to be limited in many cases. This seems to be even more true for third-generation ASMs, where very few studies have been conducted so far. Among these, the strongest evidence of the clinical utility of testing genetic polymorphisms of drug-metabolizing enzymes is for BRV and LCM, albeit with marginal clinical impact.

Furthermore, in addition to drug-metabolizing enzymes, a large number of other gene and protein regulatory processes are involved in the multiple metabolic pathways of ASMs. These actors vary according to race and can also change constantly depending on the different physiological conditions of patients. Relatively few known SNPs are capable of causing a significant change in enzyme activity, and the potential synergistic and superimposed effects of different SNPs are scarcely explored. In population pharmacokinetic studies, numerous factors other than genetics can influence drug metabolic processes.

In this regard, therapeutic drug monitoring is actually an excellent surrogate measure of the aforementioned processes, offering several advantages over the study of genetic polymorphisms, such as high accuracy, small inter-racial variations, low cost (and insurance coverage), and high feasibility.

Abbreviations

7-OH-CBD	=	7-hydroxy-CBD
AEs	=	adverse events
ASM(s)	=	antiseizure medication(s)
BRV	=	Brivaracetam
CBD	=	Cannabidiol
CBZ	=	Carbamazepine
CLB	=	clobazam
CD	=	concentration-to-dose
CYP(s)	=	cytochromes P450(s) superfamily
EM(s)	=	extensive metabolizer(s)
IM(s)	=	intermediate metabolizer(s)
LCM	=	lacosamide
LTG	=	lamotrigine
mEH	=	microsomal epoxide hydrolase
OXC	=	oxcarbazepine
PER	=	perampanel
PHT	=	phenytoin
PM(s)	=	poor metabolizer(s)
SNPs	=	single nucleotide polymorphisms
STP	=	stiripentol
UDP	=	UDP-glucurosyltransferase
VPA	=	valproic acid

Declaration of interest

P Striano has received speaker fees and participated on advisory boards for BioMarin, UCB, Neuraxpharm, and has received research funding from Jazz Pharmaceuticals, Proveca. The other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale Integrated Approach to the Study of the Nervous System in Health and Disease [DN. 1553 11.10.2022]. IRCCS ‘G. Gaslini’ is a member of ERN-Epicare. This work was also supported by the Italian Ministry of Health, RICERCA CORRENTE 2024.