Possible Role In Adrs Towards Aed Therapy

Published Date: 02 Nov 2017

The approach adopted for generating the SNP database would be to identify a panel of genes representing the major important therapeutic targets, drug transporters and DMEs. Next DNA samples from patients will be collected. Genotyping of reported SNPs would be carried out using single base pair extension method sequenom and illumina technology. Allele frequencies would be determined using relevant statistical packages. The consolidated information would be used to develop the SNP database. The relevance of the proposal is for developing a population specific SNP profile/ haplotype of critical ADR causing genes. The information generated will be a valuable tool in predicting ADRs in epileptic patients with specific old/new AEDs to identify potential new leads in the field of medicine.

4. Present knowledge and relevant bibliography including full titles of articles relating to the project.

Pharmacogenomics is the study of the genetic basis for individual differences towards drug response including both therapeutic (for drug efficacy) and adverse (for drug safety) drug effects (1). Pharmacogenomics is therefore a rapidly evolving field with certain impact on drug development and healthcare in the future. Pharmacogenomic approaches develop methodologies that can lead to DNA-based tests to improve drug selection, identify optimal dosing, maximize drug efficacy or minimize the risk of side-effects (2). Human genome map was announced way back in 2001 and has produced enormous data including more than 1.4 million single-nucleotide polymorphisms (SNPs) with over 60,000 of them in the coding region of genes. (3). Understanding the diversity and variation in the genes involved in drug response in terms of SNP frequency, distribution and density across different populations and/or ethnic groups will be vital. Human Genome Project heralded the complexities of human genetic system and has changed the impression of single gene relation with single phenotypic trait to complex networks of gene regulation and interactions (4). Therefore, multigenetic model using multiple SNPs can predict treatment outcome more reliably than single-SNP models. Based on this background, the project proposes to develop a SNP and haplotype databases for critical candidate genes involved in side effects for AEDs. Large scale association studies by genotyping many SNPs serve as promising methods for improved understanding of the basis of variable response to drugs (4). Apart from single base pair changes, other inherited changes such as insertion/deletion, duplication may also play important roles. This calls for evolving technologies which will permit high throughput SNP interrogation and which will serve as a prototype for developing diagnostics for filtering out ADRs responders and non responders. There have been significant improvements in molecular methods and genomic technologies in past few years. Based on this the role of copy number variation, methylation (‘epigenomics’) and microRNAs could not be escaped from being an important factor in complex disease etiology and drug response. In terms of genomic technologies, since last five years GWAS have revolutionized the approaches for search of new functional genetic markers (5, 6). Recent progress in molecular methods and technology have helped and will keep doing so, in covering the majority of common genetic variations and understanding the genetic architecture of many complex phenotypes.

In the context of epidemiological transition and the paradigm shift from communicable to non communicable disorders in India, epilepsy a common neurological disorder has emerged as a major public health problem (7). Based on community based surveys, a prevalence rate of 5 per 1000 person has been observed in the country, and a matter of serious concern is that the burden of epilepsy in India is nearly 20% of the global burden (7, 8). A rough estimate is that there are approximately 6 to 10 million people with epilepsy in the country (9, 10). Further about half a million new cases each year are added to the already existing number of people with epilepsy in the country. The prevalence is twice in rural areas as compared to urban areas (11). Strategy to diagnose, provide treatment and prevent epilepsy is a matter of urgent concern. Epilepsy, a paroxysmal disorder due to cerebral dysrhythmias, affects all age groups

Treatment of epilepsy is based on several factors including efficacy, safety, seizure type, concomitant drug therapy and physiological factors (12). Based on the current state of knowledge, prediction of drug dosage with optimum seizure control and no adverse drug reaction (ADR) is difficult. Therefore, it is a matter of urgent concern, and there is need to evolve a more targeted, efficacious and less harmful treatment. AED efficacy, safety and drug resistance are all multifactorially determined with influences from interactions among multiple genetic, environmental, disease related and drug related factors (13). This multifactor variability in drug response and ADR response in individual patients may be explained by means of pharmacogenetics. Pharmacogenetic studies for AED therapy will mainly focus upon genes whose products play a putatively important role in AED pharmacokinetics and pharmacodynamics i.e. drug metabolizing enzymes, drug receptors/targets and drug transporters. It is important to understand the relationship between genetic variation affecting drug metabolism (pharmacokinetics) or drug targets (pharmacodynamics) and interindividual differences in pharmacoresponse (14). Pharmacokinetics deals with the drug disposition (i.e. absorption, distribution, metabolism and excretion [ADME]) and plasma concentration whereas pharmacodynamics deals with the interaction of the drug with its target site. In terms of pharmacokinetics, clinicians conduct therapeutic drug monitoring i.e. plasma concentration estimation to get a better picture of the fate of prescribed drug in the body (13). The goal of therapy is to keep the patient completely free of seizures without drug induced ADRs. For the same reason we have pharmacological parameter i.e. therapeutic drug monitoring (TDM). TDM is necessary for achieving optimal therapy as rather than dosage, serum drug levels better correlate with therapeutic and toxic effects of drugs. Although TDM plays an important role in the management of epilepsy but cases have been reported where seizures are not controlled and patients might develop ADRs despite adequate doses, compliance and drug levels. By application of TDM for a number of AEDs optimal therapy regimen for individual patients can be determined, but all this long process might end up in debilitating patient health and socioeconomic status in the mean time (15). Relationship of genetic variants in such genes with drug levels and other clinical parameters may help in achieving an early response with better efficacy by means of pharmacogenetically optimized dosage (14).

Currently treatment regimen for epilepsy focuses on suppression of seizure prorogation and suppression of ADRs. With epilepsy as a highly heterogeneous disease the potential causes of ADRs could also be very wide. (16). Studies have shown that ADR patients imposes serious threats to patient’s life which include social impairment, reduced marriage rates and decreased life span (17).

The incorporation of pharmacogenomics into clinical drug development offers a unique opportunity for pharmaceutical companies to evaluate drugs with a better understanding of the effect that specific genetic variants will have on drug response/no response and various ADRs. With the availability of human genome sequence it is now possible to expedite the process of identification of large number of drug response-determining genetic variants by applying the tools of bioinformatics and large-scale single nucleotide polymorphism (SNP) detection and genotyping. Current estimates indicate a frequency of 1 SNP per ~300 base pairs, and 1 per ~1000 base pairs in coding regions revealing a staggering variability and making SNPs a powerful tool to establish a link between genetic variability , disease etiology and ADRs . Anticipating their usefulness in disease and health management, an international SNP Consortium has been formed for discovering SNPs throughout the genome and creates high density SNP maps. These maps will help in large-scale association studies to locate genes correlated with AEDs responsiveness/no responsiveness and side effects (25, 26, 27, 28). This study proposes to collect appropriately sized samples to detect the ADRs (such as Stevens- Johnson syndrome induced by carbamazepine) in epilepsy patients.

Some patients experience ADRs following adequate AED therapy, is a fundamental problem of many neurological diseases, but the molecular and cellular mechanisms underlying the development of ADRs are unknown. Important is to understand the genetic basis of ADRs so that we can identify subgroups of patients likely to develop ADRs in epilepsy patients.

International status

Pharmacogenomics combines the basic concept of pharmacogenetics with the powerful new tools of genomics looking at the entire spectrum of genes determining drug behavior and sensitivity in neurological disorders such as epilepsy (29). The new field of pharmacogenomics, which focuses on genetic determinants of ADRs at the level of the entire human genome, is important for development and prescription of safer and more effective individually tailored drugs.

Chronic administration of AEDs is the treatment of choice in epilepsy. Pharmacoresistant epilepsy is a major health problem, associated with increased morbidity and mortality, and accounting for much of the economic burden of epilepsy (30). A number of observational studies have attempted to identify phenotypic and genotypic markers that may be used to predict ADRs in epileptic patients. Phenotypic markers include the type of syndrome, underlying etiology, patient history of seizure frequency and density, and EEG findings.(30) Kebin Zeng, Xuefeng Wang, Zhiqing Xi, Yong Yan evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), Valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy. A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash. Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study (31). It has been shown that the HLA-B*1502 allele is strongly associated with CBZ-induced hypersensitivity reactions including Steven Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in Taiwan and Hong Kong Han Chinese(32). Another study in the Thai population also showed a strong association between HLA-B*1502 and CBZ-induced SJS (100% in 6 cases) (33) .A study in Malaysia showed that HLA-B*1502 was also present in 75% (12/16) of Malay patients with CBZ-induced SJS/TEN (34).

Table: List of genes with possible role in ADRs towards AED therapy.

Gene Name

Chromosomal location

CYP2C9

10q24

CYP2C19

10q24

CYP3A4

7q21.1

UGT1A4

2q37

HLA-B

6p21.3

National status

Study conducted by Mehta et al in 2009, revealed that out of eight patients with carbamazepine-associated Stevens-Johnson syndrome from Gujrat in India , six patients associated with HLA-B*1502 (35). Within India, the ethnic population from Kandhesh Pawra in Maharashtra in Western India, the frequency of expression of this allele is as high as 6%. In North Indian populations from Delhi and Punjab, the frequency of expression is about 1% (35, 36, 37). The rate of metabolism of DPH (Phenytoin) is genetically determined and varies by ethnicity and race. In the Tamil Nadu population, the frequency of CYP2C9 alleles viz. CYP2C9*1, CYP2C9*2, CYP2C9*3 has been established. A significant association was found between the CYP2C9 genotype and phenytoin metabolism. Carriers of either the CYP2C9*2 or *3 variant allele were found to have a two-fold higher metabolic ratio than the wild-type individuals. This is in agreement with findings from other world populations (38).