Pharmacogenetic Markers of Drug Efficacy and Toxicity.

The action of a drug is dictated by its pharmacokinetic and pharmacodynamics properties, both of which can vary in different individuals because of environmental and genetic factors. Pharmacogenetics, the study of genetic factors determining drug response, has the potential to improve clinical outcomes through targeting therapies, individualizing dosing, preventing adverse drug reactions, and potentially rescuing previously failed therapies. Although there have been significant advances in pharmacogenetics over the last decade, only a few have been translated into clinical practice. However, with new rapid genotyping technologies, regulatory modernization, novel clinical trial designs, systems approaches, and integration of pharmacogenetic data into decision support systems, there is hope that pharmacogenetics, as an important component of the overall drive towards personalized medicine, will advance more quickly in the future. There will continue to be a need for collaboration between centers all over the world, and multisector working, capitalizing on the current data revolution.

Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review.

Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug-induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future.

Personalized medicine approaches in epilepsy.

Epilepsy affects 50 million persons worldwide, a third of whom continue to experience debilitating seizures despite optimum anti-epileptic drug (AED) treatment. Twelve-month remission from seizures is less likely in female patients, individuals aged 11-36 years and those with neurological insults and shorter time between first seizure and starting treatment. It has been found that the presence of multiple seizures prior to diagnosis is a risk factor for pharmacoresistance and is correlated with epilepsy type as well as intrinsic severity. The key role of neuroinflammation in the pathophysiology of resistant epilepsy is becoming clear. Our work in this area suggests that high-mobility group box 1 isoforms may be candidate biomarkers for treatment stratification and novel drug targets in epilepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity of epilepsy are providing robust neurobiological evidence on an emerging theory of drug resistance, which may also provide new insights into disease stratification. Some of the rare genetic epilepsies enable treatment stratification through testing for the causal mutation, for example SCN1A mutations in patients with Dravet's syndrome. Up to 50% of patients develop adverse reactions to AEDs which in turn affects tolerability and compliance. Immune-mediated hypersensitivity reactions to AED therapy, such as toxic epidermal necrolysis, are the most serious adverse reactions and have been associated with polymorphisms in the human leucocyte antigen (HLA) complex. Pharmacogenetic screening for HLA-B*15:02 in Asian populations can prevent carbamazepine-induced Stevens-Johnson syndrome. We have identified HLA-A*31:01 as a potential risk marker for all phenotypes of carbamazepine-induced hypersensitivity with applicability in European and other populations. In this review, we explore the currently available key stratification approaches to address the therapeutic challenges in epilepsy.