Relationship between UGT and HLA genetic variants and adverse events associated with the use of lamotrigine. Systematic review.

Gloria Preciado Correal, Manuel Machado D., Lilian Torres T., Sandra L. Rodriguez P.

ABSTRACT


Introduction: Lamotrigine (LTG) is an aromatic antiepileptic drug, mainly used in humans in the field of neurology and psychiatry. There are secondary adverse events (AEs) related to the use of anticonvulsants, for example, toxic epidermal necrolysis (TEN) and Steven Johnson syndrome (SJS). Their incidence is estimated at 1 in 1,000 to 10,000 exposures with a mortality greater than 35%. . Objective: To describe the relationship between the presentation of adverse events and UGT and HLA polymorphisms in patients who used lamotrigine. Methodology: A systematic review of the literature was carried out, including a database search, with studies such as randomized controlled clinical trials and observational cohort and case-control studies. Results: The initial search found a total of 96 articles. After applying the inclusion and exclusion criteria, only 8 were considered. Conclusions: At the time of the development of this study, there was not enough evidence to relate HLA and UGT variants as a causal factor to predict adverse events (AEs) due to the use of lamotrigine. Furthermore, it is important to say that in Colombia there are no studies, and that we do not know these genetic variants, therefore it is not possible to extrapolate it. Thus the recommendation is that studies should be carried out in the Colombian population using variants proposed as possibly relating AEs. to lamotrigine.

Keywords: pharmacokinetics, lamotrigine, polymorphism, glucuronosyltransferase, HLA, adverse event.

INTRODUCTION


Since the Human Genome Project in 1990, molecular biology has made significant progress in pharmacogenetics(1,2) which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy—the topic addressed here—is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics. Lamotrigine (LTG) is a drug that is part of the aromatic antiepileptics group, and its main uses in humans are in the field of neurology and psychiatry. An adverse event is “any undesirable event experienced by a patient, regardless of whether it is suspected or not, to be related to administered medication”(3). For lamotrigine, the origin of adverse events (AEs) has been associated with some genetic variations that will condition the interindividual variation and the metabolism of lamotrigine(4). Mainly two types of AEs have been described: cutaneous and related to their pharmacokinetics. From mild maculopapular skin reactions to severe organic involvement and death, including toxic epidermal necrolysis (TEN) and Steven Johnson syndrome (SJS), non-bullous skin reactions, in pharmacokinetics, to an increase in serum concentration associated with HLA and UGT genetic variants (8- 10) uno de cada mil pacientes hospitalizados sufren reacciones adversas que amenazan la vida. Las reacciones adversas a medicamentos, denominadas como reacciones alérgicas (inmunológicas.

The incidence of severe cutaneous AEs such as SJS and TEN due to anticonvulsants is estimated at 1 in 1,000 to 10,000 exposures with a mortality greater than 35%(8) Stevens-Johnson syndrome, and toxic epidermal necrolysis and are a global public health problem associated with the use of antiepileptic drugs (AEDs. Until the end of the search, there are no studies on the incidence of AEs with lamotrigine in Colombia. Due to the lack of knowledge of the frequency of AEs related to genetic variabilities, the objective of this study is to describe the relationship between adverse events and UGT and HLA polymorphisms in patients who used lamotrigine, through a systematic review of the literature of the last 5 years of studies of patients with UGT and HLA variants who have presented AEs related to the use of lamotrigine.

METHODOLOGY


A systematic literature review, including a search in the databases, with studies such as randomized controlled clinical trials and observational cohort, case-control studies, as well as meta-analyses were performed. The search was carried out in Cochrane, Embase, PubMed, NHL and LILACS, using the MeSH terms, the search descriptors were “genetic polymorphism” OR “pharmacogenomics” AND “adverse effects” AND “lamotrigine”. The language was restricted to Spanish and English. Additionally, the references of the included articles were used to search for other relevant studies. Unpublished studies were not considered. Subsequently, the titles and abstracts were screened, selecting the most relevant studies. The quality of the studies was evaluated based on the Cochrane manual of systematic reviews of interventions. Studies that included people who have UGT and HLA variant polymorphisms, and who presented adverse effects with the use of lamotrigine were selected. The studies included people from any background, of any sex and ethnic origin, who had received a prescription for LTG. The ROB2 scale was used to evaluate bias control.

The core outcome measures were taken from several articles describing the clinical classification of drug-induced skin reactions. Articles from the RegiSCAR (European Registry of Serious Cutaneous Adverse Reactions) consortium will be included(11).

The article search formula used to search for articles consisted of: (“lamotrigin”[All Fields] OR “lamotrigine”[MeSH Terms] OR “lamotrigine”[All Fields] OR “lamotrigine s”[All Fields]) AND (“polymorphism, genetic”[MeSH Terms] OR (“polymorphism”[All Fields] OR “genetic”[All Fields]) OR “genetic polymorphism”[All Fields] OR (“genetic”[All Fields] OR “polymorphism “[All Fields])) AND (“adverse effects”[MeSH Subheading] OR (“adverse”[All Fields] OR “effects”[All Fields]) OR “adverse effects”[All Fields])

Data extraction and quality evaluation.

From each selected article, the following data was extracted: First author, year of publication, population, study design, type of adverse event, identification of variants, relationship with the adverse event. According to the selected articles, the AMSTAR scale was used for the quality assessment of systematic reviews(12), and the Newcastle-Ottawa scale for observational cohort and case-control studies. This scale evaluates three aspects: selection, comparability, and exposure or outcome(13).

Two authors (MP, SR) independently screened all titles and abstracts of publications identified through the searches. Articles with discrepancies were resolved by consensus, and if the discrepancies continued, they were revised by a third reviewer (MEMD) to finish selecting the initial articles. After this review, an analysis of the full text was carried out. Then out of those preselected studies, the final inclusion was defined in a in the systematic review according to the established inclusion criteria. (Table 2 and 3).

RESULTS


The initial search found a total of 96 articles of which 8 remained after applying the inclusion and exclusion criteria and a full text review (figure 1). The characteristics of the included studies are shown in Table 1. In the general identified results, the study by Ying Chang et al (2014)(14) and the study by Yafag Zhou et al (2015)(15) show an increase in lamotrigine concentration associated with UGT variants in the study by Hye Jung Park (2016)(16) lamotrigine, carbamazepine and describes the association of HLA variants with the presentation of SJS and TEN. Regarding case-control studies, the study by Celeste et al (2007)(17), Frike-galindo y cols (2014)(18)this has not been investigated in Mexican Mestizos (MM, Ramírez et al (2016) (19) such as Stevens-Johnson syndrome (SJS, describe the relationship between SJS, TEN and HLA variants. Finally, 2 systematic reviews were included, Deng and cols 2018 (20), Wanshu and cols 2020(21) we conducted a systematic review and meta-analysis. METHODS: We performed a comprehensive search of the literature in several electronic database systems including Cochrane Library, EMBASE and PubMed from inception to January 2020. Review Manager was used to compare the frequencies of HLA-A•24:02 carriers between the subgroups. RESULTS: A total of 5 studies were eligible, including 197 LTD-cADRs, 396 LTD-tolerant controls, and 2068 population controls. Compared with the LTG-tolerant controls, there was a statistically significant association between the HLA-A•24:02 allele and LTG-induced cADRs (odds ratios: 1.94, 95% confidence intervals 1.06-3.54; P = .03, with evaluation results on the high and medium AMSTAR scale, respectively. In order to meet the objectives of the review, observational studies were included, consisting of 3 cohort studies and 3 case-control studies, which had a score equal to or greater than 7, low risk of bias, on the New Castle scale. -Ottawa (NCO), (Table 2 and 3).

Adverse skin reactions

In the systematic review with meta-analysis carried out by Deng et al in 2018(20), of a total of 174 initial studies identified in the databases, 11 studies of the Chinese, Korean and Thai population were included. All studies are assessed by the NCO scale with a score greater than 5, are case-control studies based on an Asian population and include 73 patients using LTG and SJS/TEN, 144 patients with maculopapular erythema (ME) and 426 patients with tolerance to LTG. The diagnosis of SSJ/NET was made based on the criteria of Roujeay and Stern. EM was defined as pink macules that usually resolve 1-2 weeks after the suspension of the medication. The association between HLA-B*1502 and the induction of RAC was found in a total of 7 studies where there was no significant association between patients carrying HLA-B*1502 and EM induced by LTG (OR 1.07, IC : 95% 0,59-1,95, P=0,82). While HLA-B*1502 turned out to be a risk allele for SSJ/NET induced by LTG (OR 2.4, 95% IC: 1,20-4,78, P=0,01).

For the analysis of HLA-B*2402, 2 studies were included where a significant association was presented between patients carrying this variant and EM (OR 2.14, 95% CI: 1.10-4.16, P=0.03), also an increased risk for SSJ/NET was observed (OR 3.50, 95% CI: 1,61-7,59, P=0,02). Regarding HLA-B*3303, it was identified in 4 patients as a protective factor for EM (OR 0.2, 95% IC: 0.06-0.64, P=0.007) and from HLA-B*5801 in EM no statistically significant relationship was found (OR 1.03, 95% CI: 0,39-2,72, P=0,95). The Wanshu 2020 systematic review with meta-analysis(21) we conducted a systematic review and meta-analysis.

METHODS


We performed a comprehensive search of the literature in several electronic database systems including Cochrane Library, EMBASE and PubMed from inception to January 2020. Review Manager was used to compare the frequencies of HLA-A•24:02 carriers between the subgroups. RESULTS: A total of 5 studies were eligible, including 197 LTD-cADRs, 396 LTD-tolerant controls, and 2068 population controls. Compared with the LTG-tolerant controls, there was a statistically significant association between the HLA-A•24:02 allele and LTG-induced cADRs (odds ratios: 1.94, 95% confidence intervals 1.06-3.54; P = .03 , describes the relationship between the HLA-A•24:02 variant and the presence of cutaneous adverse reactions (RAC). According to the inclusion criteria in the data bases, a total of 103 documents were identified. Finally, a total of 5 case control studies were included, with a population of 2661 people, where 197 patients had an adverse reaction, 396 tolerated the use of lamotrigine, and 2068 were controls. RACs were clearly identified in 3 of 5 studies. The studies were carried out in Norway, Korea, and China. These studies used the NCO quality scale, with scores between 5 and 6. The statistical relationship between the HLA-A•24:02 allele and the RAC had an (OR: 1.94, CI 95% 1.06-3.54; P=0.03), a random effects model was used due to the high heterogeneity (I2: 56%, P=0.04) in the 5 included studies. This led to conclude that the HLA-A•24:02 variant shows a statistically significant association to develop ACR with lamotrigine.

The retrospective cohort study done by Hye Jung Park et al (2016)(16) lamotrigine, carbamazepine, in which 5802 users of different medications at high risk of inducing SJS/TEN such as LTG were taken, and which had HLA prior to the start of the study, between August 2005 and July 2014. Of the 25 lamotrigine users, 7 (28.0%) developed SJS/TEN. Among them, 3 patients (42.9%) had the HLA-B*44:03 allele. Furthermore, 18 of the lamotrigine users were tolerant to the drug, only one subject (5.6%) had the HLA-B*44:03 allele. It was found when performing the analysis that HLA-B*44:03 may be associated with SJS/TEN induced by lamotrigine (OR: 12,75; IC 1,03-157,14; p=0,053).

Man Celeste et al (2007)(17) in a case-control study where 72 patients from the Prince of Wales Hospital in Hong Kong, China were included, determined HLA-B genotypes, and a total of 24 cases that developed RAC were identified. 8 weeks after starting aromatic antiepileptics (AA), carbamazepine, phenytoin and lamotrigine were evaluated and their relationship with the HLA-B*1502 marker was analyzed. In order to analyze the cases, they were divided into two groups: patients with severe skin reactions, and patients with maculopapular rash, and also categorized by the active ingredient of the medication in use. Follow-ups for patients with similar treatment with aromatic antiepileptics for at least 3 months, with no history of drug-induced ADR. RAC was related to the HLA-B•502 variant polymorphism (75.0% cases vs. 14,5% follow ups, p=0,001; OR 17,6, CI 95% 2,9–105,2). Of the patients using lamotrigine (n=2), 1 presented the described variant and severe skin reactions, and 4 presented maculopapular rash. It was concluded that there is a relationship between RAC and the use of AA and the HLA-B*1502 variant.

In the case-control study by Ingrid Fricke-Galindo et al (2014)(18)this has not been investigated in Mexican Mestizos (MM, Mexican mestizo patients were selected from an epilepsy clinic in that country, with a total population of 290 participants. The cases were 69 patients using phenytoin, carbamazepine, and lamotrigine who had RAC and HLA variant, and 225 controls who were patients using AA for 1 year without RAC with HLA variants. Of a population of 28 patients using lamotrigine, 14 patients presented ACR and had the variants HLA-A*02:01:01/- B*35:01:01/-C*04:01:01. This is the first investigation of HLA class I alleles associated with ACR induced by AA in a Mexican mestizo population. The haplotype HLA- A*02:01:01/ B*35:01:01/ C*04:01:01; (OR: 11.20; IC: 95% 3.54–35.48) appears to be a biomarker for LTG-induced maculopapular rash in patients with MM. It is also the first time that an association of this haplotype with AA-induced RAC has been reported in any population(18) this has not been investigated in Mexican Mestizos (MM).

In the study carried out by Elena Ramírez et al (2016)(19) such as Stevens-Johnson syndrome (SJS, a total of 67 patients who were taking lamotrigine and who presented ACR (SJS/TEN) were defined as cases; and three different groups as controls. (A) tolerant to 1 AA (B) tolerant to any AA (C) Spanish patients awaiting an unrelated hematopoietic stem cells transplant. There were 6 cases in group A, 1 case compared to B. 9 cases in group C. The HLA genotypes of SJS/TEN were differentiated by AA type, with relation to lamotrigine, the most frequent genotype is HLA-B*38:01 (3 carriers out of 3 cases, 100%) and was significantly higher in the LTG-induced SJS/TEN group (CI: 95% 38–100) and in the SJS/TEN group Phenytoin (PHT)-LTG (5 carriers out of 12 cases, 41.7%) compared to the 3 control groups. It should be noted that all 3 cases were carriers of this allele, and none of the individuals in the LTG-tolerant group were carriers of HLA-B*38:01. For DRESS, HLA-A*24:02 was identified with 3 carriers out of 3 cases (100%) and in the PHT-LTG formulation there were 6 carriers out of 8 cases (75%) compared to the control group (p =0.080). Therefore, the development of RAC was correlated with the HLA-B*38:01 variant, and significant associations were identified between AA-induced SJS/TEN that are different from those found for AA-induced DRESS. The HLA-A*24:02 variant was also identified as a risk factor for SJS/TEN induced by AA or DRESS in the Spanish Caucasian population.

The study carried out by Chang et al in (2014) (14) where a cohort of 106 patients with epilepsy was evaluated at the Julin hospital, China, between June 2011 and September 2012, who received monotherapy with LTG. , their blood levels of LTG and the markers UGT1A4 (70C?A) and UGT1A4(142 T?G) were measured, with these measurements the therapeutic efficacy of LTG was evaluated within 1 year of one year. The results showed that all patients were homozygous for the CC genotype of UGT1A4 (70C>A), while the distribution of UGT1A4 (142 T>G) varied among patients. Two patients had a single nucleotide deletion at position 127 (UGT1A4 127delA). To evaluate the effect of the UGT1A4 (142 T>G) variant on the pharmacokinetics of LTG, patients were divided into two groups. Group A included patients with the 142TG or 142GG variant and patients in Group B had the 142TT variant in Group B. The normalized blood concentration and efficacy of LTG were higher in patients in Group B than in those in Group B. Group A (P<0.05). The two patients with the UGT1A4 127 del A genotype had extremely high blood levels of LTG, and treatment was discontinued in one of these patients due to a severe LTG-associated rash. In conclusion, patients with the UGT1A4 142TT variant had a higher concentration of LTG in the blood and better therapeutic efficacy, suggesting that this variant influences the activity of LTG.

In the study by Yafang Zhou et al (2015)(15), a total of 140 patients with epilepsy, from the neurology service of Sun Yat-sen hospital in China, were treated with LTG at doses of 37.5-250 mg per day as monotherapy between 2012 and 2014 . Genotyping analysis for the UGT2B7, ABCB1, ABCG2, NR1I2 and HNF4? variants was performed on all patients and was correlated with the blood concentration of LTG. Genotyping analysis for the UGT2B7, ABCB1, ABCG2, NR1I2 and HNF4? variants was performed on all patients and was correlated with the blood concentration of LTG. Subsequently, LTG concentrations were taken and correlated with the genetic markers previously described. Using a regression model, the data analysis was carried out concluding that the variants in ABCG2 rs2231142, rs3114020, HNF4a rs2071197 (p = 0.009, p = 0.031 and p = 0.036, respectively) With statistical analysis with coefficient of determination R2=0.465. It conclusion, these variants can influence the blood concentration of LTG and must be taken into account for dose adjustment.

DISCUSSION AND CONCLUSIONS


The final findings of this study describe the possibility that genetic variants are a risk factor to present signs of ACR and may lead to an increase in the blood concentration of the drug; however, a causal relationship could not be established, since the presence of AEs is of multifactorial origin and the findings of these studies do not allow establishing a causal relationship. It is also important to highlight that these findings are important due to the high morbidity generated by ADRs and the repercussions on pharmacokinetics that can occur with the use of lamotrigine(22-25) Stevens-Johnson syndrome, and toxic epidermal necrolysis, we needed to define criteria for classifying the cases and standardize the collection of data so that cases could be reliably diagnosed according to this classification. Based on review of case histories and photographs of patients, a group of experts proposed a classification based on the pattern of erythema multiforme—like lesions (categorized as typical targets, raised or flat atypical targets, and purpuric macules. To be certain of this possible relationship, it would be necessary to have new studies that evaluate and differentiate each risk factor. For example, in adverse skin reactions such as SJS and TEN, patient comorbidities, age, and genetic factors, among others, have been identified as risk factors(24). The present study may be of help for patients using lamotrigine and for treating physicians, by having more evidence of the clinical interpretation of AEs due to the use of lamotrigine, and the most accurate, safe, and personalized use of this medication.

In the 8 studies that were included, it is evident that the populations where the AEs that used lamotrigine were found and that describe some variants in UGT and HLA as a genetic risk factor, are all within in the Asian population. In only one study with a different population (Mexican), it was not possible to determine that they can be used as genetic markers in other different populations, since they are already characteristics of these groups(26).

Thus, leading to the need to generate new evidence and new studies in unevaluated populations that allow extrapolating the information found in these studies. What represents these variations in the genotype of these populations, is the susceptibility that the studied populations must present AEs with the use of lamotrigine(4) thus, in this case the results will be applicable to the population of East Asia and Mexico.

It is important to highlight that when looking at the worldwide reports on the vigiaccess pharmacovigilance page(27), until May 2022, 63,425 adverse reactions to lamotrigine have been reported, 22,118 (17%)of them are cutaneous. It is striking to see that Asia has more genetic studies and reports, but fewer AEs associated with lamotrigine (12%), compared to America, which is the continent that has reported the highest percentage of adverse reactions to lamotrigine with 57% of the total adverse reactions reported worldwide. Hence, highlighting the importance of conducting pharmacogenetic studies with lamotrigine in American populations.

Most included studies came from China and East Asia, where, for example, there is a prevalent use of anticonvulsants in China and is increasing in pediatric population going from 6,170 prescriptions in 2013 to 8,211 prescriptions in 2018 (20). New anticonvulsant medications (ACM) were prescribed more than the old ones during this period. Among these new ACMs is lamotrigine. Surprisingly, it was the only one that showed a decreased use during this study, compared to the other new ACMs(28)and to provide real-world evidence on medicine utilization of pediatric patients with epilepsy in China. Methods: ASM prescriptions for pediatric patients written from 2013 to 2018 were extracted from the database of the Hospital Prescription Analysis Cooperative Project. Trends of ASM use were analyzed by total prescriptions, cost, age, sex, ASM class and specific ASM. Prescribing patterns of ASMs were also analyzed. Results: A total of 44,675 ASM prescriptions were extracted for analysis in this study. Throughout the study period, a slight increase of ASM prescriptions was observed from 6170 in 2013 to 8211 in 2018. Children aged between 6 and 18 years, accounted for 78 % of total prescriptions every year. ASM use in boys was about 1.5 times higher than that in girls. Newer ASMs were prescribed more than older ASMs during this period. Sodium valproate was the most frequently prescribed ASM in 2013, and its use decreased in girls in 2016. Levetiracetam increased from 19.10 % in 2013 to 28.09 % in 2018 and became the most common ASM at the end of this study. Meanwhile, the use of oxcarbazepine increased from 19.31 % to 22.04 %, whereas the use of lamotrigine had declined from 18.43 % to 10.72 %. Monotherapy (66.24 %). This leads us to think that it is possible that the findings on genetic susceptibility in this population have influenced this prevalence of use, since it was concluded that the most prescribed new ACMs are those that have fewer side effects and drug interactions(28)and to provide real-world evidence on medicine utilization of pediatric patients with epilepsy in China. Methods: ASM prescriptions for pediatric patients written from 2013 to 2018 were extracted from the database of the Hospital Prescription Analysis Cooperative Project. Trends of ASM use were analyzed by total prescriptions, cost, age, sex, ASM class and specific ASM. Prescribing patterns of ASMs were also analyzed. Results: A total of 44,675 ASM prescriptions were extracted for analysis in this study. Throughout the study period, a slight increase of ASM prescriptions was observed from 6170 in 2013 to 8211 in 2018. Children aged between 6 and 18 years, accounted for 78 % of total prescriptions every year. ASM use in boys was about 1.5 times higher than that in girls. Newer ASMs were prescribed more than older ASMs during this period. Sodium valproate was the most frequently prescribed ASM in 2013, and its use decreased in girls in 2016. Levetiracetam increased from 19.10 % in 2013 to 28.09 % in 2018 and became the most common ASM at the end of this study. Meanwhile, the use of oxcarbazepine increased from 19.31 % to 22.04 %, whereas the use of lamotrigine had declined from 18.43 % to 10.72 %. Monotherapy (66.24 %. In the United States, ACM prescriptions for the management of psychiatric pathologies in the pediatric population have also increased from 33% to 68% in a measured period of 14 years (29).

In adults, the prevalence of ACM use was measured in China from 2013 to 2018, where increase in its use was evident, going from 28,360 prescriptions in 2013, to 44,110 prescriptions in 2018. This increase in prescriptions raised health care costs from approximately 57,228,401 US dollars in 2013 to 100,493,433 US dollars in 2018(30)767 prescriptions from 60 hospitals were eligible and extracted for analysis. The number of ASM prescriptions increased from 28,360 in 2013 to 44,110 in 2018, and the corresponding cost increased from 9,452,990 Chinese Yuan (CNY. The use of lamotrigine for the management of bipolar affective disorder, has also increased from 14.7% to 37.2%(31). The increased prevalence of lamotrigine use may lead to an increase in AEs in all populations, especially potential severe skin reactions. In other places, such as Brazil, there is an increase in the prescription of lamotrigine from 5.5% to 33.6% for the treatment of epilepsy in people over 60 years old)(32). In Colombia, studies on the use of anticonvulsants prescribed for and in doses other than those initially planned were found. Monotherapy was the most used therapeutic approach, which, added to the use of classic antiepileptic drugs, expands its use and the number of doses of ACM used. (2,33,34)J. E. Calvo-torres L.F, Garcia-Betancur S., Aguirre-novoa A”,”given”:”Bañol-Giraldo A.M”,”non-dropping-particle”:””,”parse-names”:false,”suffix”:””}],”container-title”:”Neurologia”,”id”:”ITEM-1”,”issue”:”2”,”issued”:{“date-parts”:[[“2016”]]},”page”:”89-96”,”title”:”Estudio de prescripción-indicación en pacientes que reciben antiepilépticos en Colombia”,”type”:”article-journal”,”volume”:”31”},”uris”:[“http://www.mendeley.com/documents/?uuid=9c606db9-9d4d-48f4-b557-07b1d4c848fe”]},{“id”:”ITEM-2”,”itemData”:{“DOI”:”10.22379/2422402219”,”ISS”:”01208748”,”abstract”:”Introduction: Epilepsy is a common neurological condition with an estimated incidence of 50 per 100,000 population and a prevalence five to ten per 1,000 population in developed countries. It is considered refractory when seizures are so frequent that the patient’s ability to live fully is limited, when treatment does not control seizures, or when side effects are limiting for the normal development of the person. Lamotrigine is an antiepileptic drug that inhibits the sodium channel voltage-dependent presynaptic modulating excitatory transmitter glutamate and aspartate type. Objective: To determine the effectiveness of Lamotrigine as monotherapy or in combination with conventional antiepileptic drugs in patients with refractory epilepsy. Materials and methods: A descriptive study. Period May 2009 to November 2012. Variable analysis by frequency, averages and ratios. Results: Sample: 115 medical records. 97.4% (112. As the increase in the prevalence of ACM use, evidently raised costs, new studies should be developed relating adverse reactions and costs of care in the region, not only due to the direct cost of the medications but also due to possible complications.

Pharmacogenetics enables medical tailoring treatments to an individual’s genetic predisposition applied to pharmacology, which can improve treatment outcomes and reduce costs.(34)promising individualized drug selection and dosing. Traditionally, pharmacogenetic profiling has been performed using targeted genotyping that focuses on common/known variants. Recently, whole-genome sequencing (WGS By focusing on the most common variants with a functional prediction in a particular population and detecting pharmacogenes, we improve drug safety and reduce experimentation in drug selection. (35) This may suggest that the costs of processing individualized genetic tests may be lower than the costs of in-hospital medical care.

This study has some limitations, such as the type of population included, because it is predominantly East Asian, which does not allow the data to be extrapolated to other populations due to their own genetic characteristics. Not all languages were included, so we may not have found other studies that meet the inclusion criteria of this review. No clinical trials were found, and observational studies were included; however, in the bias assessment, they all are considered studies with low bias risk. The studies made a bivariate evaluation of the RAC and the genetic variations without including a model adjustment for the other possible associated confounding factors, thus there is an information bias on this point. The strengths of this study include the inclusion of two systematic reviews with favorable results in the evaluation of biases. Studying the topic of pharmacogenetics in the country, shows a pioneering interest. This study was carried out by a multidisciplinary team that gave adequate development to the study. In addition, all included studies presented a low bias risk and the searches were carried out using international reference biomedical databases.

In conclusion, one of the most important findings of this literature systematic review, is that at the time of its development, there is not enough evidence to relate the HLA and UGT variants as a casual factor to the prediction of AEs with the use of lamotrigine. However, in Deng’s studies 2018(20) and Wanshu 2020(21) we conducted a systematic review and meta-analysis. METHODS: We performed a comprehensive search of the literature in several electronic database systems including Cochrane Library, EMBASE and PubMed from inception to January 2020. Review Manager was used to compare the frequencies of HLA-A•24:02 carriers between the subgroups. RESULTS: A total of 5 studies were eligible, including 197 LTD-cADRs, 396 LTD-tolerant controls, and 2068 population controls. Compared with the LTG-tolerant controls, there was a statistically significant association between the HLA-A•24:02 allele and LTG-induced cADRs (odds ratios: 1.94, 95% confidence intervals 1.06-3.54; P = .03, conducted in East Asia, showed that there was a greater probability fort the HLA-B*1502, HLA-A*02:01:01/- B*35:01:01/-C*04:01:01 variants to increase susceptibility and present RAC with the use of lamotrigine, in addition to the studies Chang et al (2014)(14) and Yafang Zhou (2015)(15), conducted in China, related the increase in lamotrigine concentration to variants in the UGT.

This requires more in-depth studies considering the multicausality of the different risk factors, population, age, environment, comorbidities, among others, that can determine the magnitude of these associations. Furthermore, it is important to say that in Colombia there are no studies, and that we do not know these genetic variants, therefore the extrapolation could not be carried out, leading to recommend that studies should be carried out in the Colombian population with the variants proposed as possible related to lamotrigine RAC.

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HOW TO QUOTE?


(2024). Relationship between UGT and HLA genetic variants and adverse events associated with the use of lamotrigine. Systematic review..Journal of Neuroeuropsychiatry, 57(4).
Recovered from https://www.journalofneuropsychiatry.cl/articulo.php?id= 173
2024. « Relationship between UGT and HLA genetic variants and adverse events associated with the use of lamotrigine. Systematic review.» Journal of Neuroeuropsychiatry, 57(4). https://www.journalofneuropsychiatry.cl/articulo.php?id= 173
(2024). « Relationship between UGT and HLA genetic variants and adverse events associated with the use of lamotrigine. Systematic review. ». Journal of Neuroeuropsychiatry, 57(4). Available in: https://www.journalofneuropsychiatry.cl/articulo.php?id= 173 ( Accessed: 13junio2024 )
Journal Of Neuropsichiatry of Chile [Internet]. [cited 2024-06-13]; Available from: https://www.journalofneuropsychiatry.cl/articulo.php?id=173

 

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