Promise Of Pharmacogenetics Research Articles

Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics.

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

A Need for Evidence-Based Answers to Coagulation and Pharmacogenetics

The role of global coagulation assays in the clinical setting is unclear. Clinical trials are needed to further assess the relationship between global assays and clinical bleeding. Despite the promise of pharmacogenetics, evidence-based trials are needed to clarify the association between genotype and clinical outcomes, especially related to warfarin.

Zinc-rs13266634 and the arrival of diabetes pharmacogenetics: the "zinc mystique".

Advances in our understanding of the genetics of type 2 diabetes have been astronomical over the past decade with more than 100 single nucleotide polymorphisms (SNPs) associated with modest increases in diabetes risk and differences in related traits such as fasting glucose (1,2). However, these SNPs have contributed more to elucidating biologic pathways than predicting diabetes risk (3). Nonetheless, the most promising work suggests that we are on the cusp of being able to use genetic information to individualize treatment for type 2 diabetes prevention and management (4,5). The promise of pharmacogenetics is predicated on the existence of known individual variation in response to interventions and the strong biologic basis for genetic variation as a primary, immutable difference between individuals. rs13266634 is one of the most consistently replicated diabetes risk variants (odds ratio of 1.14 for the R allele) (6). This SNP encodes a C→T base substitution in the SLC30A8 gene, resulting in a change in the coded protein (Arg325Trp or R325W). The frequency of the diabetes risk R allele is 91.5%, 71.7%, and 56.7% in Africans, Europeans, and Asians, respectively (1,000 Genomes). The SLC30A8 gene encodes zinc transporter-8 (ZnT8). This transporter is specific to pancreatic islets and is …

Pharmacogenetics in dermatology: a patient‐centered update

The term pharmacogenetics is used to describe an evolving field that aims to understand the relationship between individual variations in genetic sequence and differences in the therapeutic and toxic response to medications. The promise of pharmacogenetics is empowerment of clinicians with information that will enable them to personalize drug therapy - to prescribe the right medication at the right dose for each patient, while minimizing adverse effects. Despite dramatic advances, wide application of pharmacogenetics to clinical practice has been slow for a number of reasons, including lack of evidence-based therapeutic guidelines as well as ethical concerns and cost. To illustrate applications to dermatology practice, we present three clinical scenarios that serve as a springboard for discussion of the principles of pharmacogenetics and how they can be used to guide treatment with azathioprine, 5-fluorouracil, and trastuzumab. The therapeutic and toxic effects of a given medication ultimately depend on its combined pharmacokinetic, pharmacodynamic, and pharmacogenetic properties in a given individual. Pharmacodynamic properties of individual medications must be correlated with single nucleotide polymorphisms. Test recommendations and standardization of therapy for specific disorders can then be established.

Ready When You Are: Easing Into Preemptive Pharmacogenetics

The promise of pharmacogenetics has included reduction of adverse drug events and enrichment for clinical efficacy. However, there has been very little assessment of the context in which this promise could be delivered. There are issues of return on effort and end points of meaningful impact that are crucial to moving this area of clinical pharmacology into practical benefit for our health system.

Cytochrome P450 3A Polymorphisms and Immunosuppressive Drugs: An Update

Among the immunosuppressive drugs currently used in solid-organ transplantation, the calcineurin inhibitors cyclosporine and tacrolimus, and the mammalian target of rapamycin inhibitors sirolimus and everolimus, may be difficult to use because of large interindividual variability in their pharmacokinetic characteristics and a narrow therapeutic index. The promise of pharmacogenetics and pharmacogenomics is to elucidate the inherited basis of differences between individual responses to drugs, in order to identify the right drug and dose for each patient. As cytochrome P450 (CYP)3A4 and CYP3A5 are both involved in the metabolism of these drugs, the consequences of the polymorphism of these genes have been studied. It has been recently shown that the CYP3A5*3 polymorphism is associated with pharmacokinetics of tacrolimus and sirolimus. The association between the CYP3A4 and CYP3A5 polymorphisms and cyclosporine pharmacokinetics is more questionable. It is now of utmost importance to prospectively test these initial results to improve the individualized use of these drugs.

The promise of pharmacogenetics: assessing the prospects for disease and patient stratification

Pharmacogenetics is an emerging biotechnology concerned with understanding the genetic basis of drug response, and promises to transform the development, marketing and prescription of medicines. This paper is concerned with analysing the move towards segmented drug markets, which is implicit in the commercial development of pharmacogenetics. It is claimed that in future who gets a particular drug will be determined by their genetic make up. Drawing on ideas from the sociology of expectations we examine how pharmaceutical and biotechnology companies are constructing, responding to and realising particular ‘visions’ or expectations of pharmacogenetics and market stratification. We argue that the process of market segmentation remains uncertain, but that the outcome will be fashioned according to the convergence and divergence of the interests of key commercial actors. Qualitative data based both on interviews with industry executives and company documentation will be used to explore how different groups of companies are developing pharmacogenetics in distinct ways, and what consequences these different pathways might have for both clinical practice and health policy. In particular, the analysis will show a convergence of interests between biotechnology and pharmaceutical companies for creating segmented markets for new drugs, but a divergence of interest in segmenting established markets. Whilst biotechnology firms have a strong incentive to innovate, the pharmaceutical industry has no commercial interest in segmenting markets for existing products. This has important implications, as many of the claimed public health benefits of pharmacogenetics will derive from changing the prescribing of existing medicines. One significant implication of this is that biotechnology companies who wish to apply pharmacogenetics to existing medicines will have to explore an alternative convergence of interests with healthcare payers and providers (health insurers, HMOs, MCOs and national health systems). Healthcare providers may have a strong incentive to use pharmacogenetics to make the prescribing of existing medicine more cost-effective. However, we conclude by suggesting that a question mark hangs over their ability to provide the necessary economic and structural resources to bring such a vision to fruition.

Use of pharmacogenetics in clinical medicine: hype or hope?

The dawn of the new millennium saw numerous articles (particularly in the lay and financial press) on the promise of pharmacogenetics and personalized drug therapy. These articles promised that genetic information would be used regularly to help guide drug therapy decisions in the near future. Simultaneously, a number of small biotechnology companies focused their energies on making this promise a reality. So where are we, now that 5 years have passed, and we are at the point in time when such advances were promised to be in regular use? We are clearly not where these articles had predicted. The number of pharmacogenetic tests being used in clinical practice has increased since that time, but the number of available tests remains limited to a handful, and their use in practice remains a rare event. In addition, many of the companies focused on pharmacogenetics in 2000 are either no longer in existence, or have refocused their attention on other problems. So what happened? Has pharmacogenetics failed to meet the promise? Will we ever see the day when genetic information is used on a regular basis to guide drug therapy selection and dosing? Certainly, pharmacogenetics has failed to deliver the promise of regular use in clinical practice by the mid-2000s. This is probably explained by several factors, the first of which being an unrealistic timeline for the accomplishment of such goals, particularly among the lay media. Additionally, the task has proved to be more challenging than many expected. This is explained in part by the dramatic advances prior to 2000 in genetics and pharmacogenetics, which stemmed from examples of single genes in which polymorphisms resulted in dramatic phenotypic differences. However, understanding the genetic basis for common, complex diseases and most drug responses has been more challenging due to the involvement of multiple genes, each of which may contribute in small ways to the phenotype. Nonetheless, there

Inheritance and drug response.

he promise of pharmacogenetics, the study of the role of in heritance in the individual variation in drug response, lies in its potential to identify the right drug and dose for each patient. Even though individual differences in drug response can result from the effects of age, sex, disease, or drug interactions, genetic factors also influence both the efficacy of a drug and the likelihood of an adverse reaction. 1-3 This article briefly reviews concepts that underlie the emerging fields of pharmacogenetics and pharmacogenomics, with an emphasis on the pharmacogenetics of drug metabolism. Although only a few examples will be provided to illustrate concepts and to demonstrate the potential contribution of pharmacogenetics to medical practice, it is now clear that virtually every pathway of drug metabolism will eventually be found to have genetic variation. The accompanying article by Evans and McLeod 4 expands on many of the themes introduced here. Once a drug is administered, it is absorbed and distributed to its site of action, where it interacts with targets (such as receptors and enzymes), undergoes metabolism, and is then excreted. 5,6 Each of these processes could potentially involve clinically significant genetic variation. However, pharmacogenetics originated as a result of the observation that there are clinically important inherited variations in drug metabolism. Therefore, this article — and the examples highlighted — focuses on the pharmacogenetics of drug metabolism. However, similar principles apply to clinically significant inherited variation in the transport and distribution of drugs and their interaction with their therapeutic targets. The underlying message is that inherited variations in drug effect are common and that some tests that incorporate pharmacogenetics into clinical practice are now available, with many more to follow. The concept of pharmacogenetics originated from the clinical observation that there were patients with very high or very low plasma or urinary drug concentrations, followed by the realization that the biochemical traits leading to this variation were inherited. Only later were the drug-metabolizing enzymes identified, and this discovery was followed by the identification of the genes that encoded the proteins and the DNA-sequence variation within the genes that was associated with the inherited trait. Most of the pharmacogenetic traits that were first identified were monogenic — that is, they involved only a single gene — and most were due to genetic polymorphisms; in other words, the allele or alleles responsible for the variation were relatively common. Although drug effect is a complex phenotype that depends on many factors, early and often dramatic examples involving succinylcholine and isoniazid facilitated acceptance of the fact that inheritance can have an important influence on the effect of a drug. Today there is a systematic search to identify functionally significant variations in DNA sequences in genes that influence the effects of various drugs. 4 t

PHARMACOGENETICS AND PHARMACOGENOMICS

This article introduces pharmacogenetics and pharmacogenomics in the context of pharmacotherapy in the pediatric ICU setting. As an independent discipline (if it can be considered as such), pediatric or developmental pharmacogenetics is essentially at a neonatal stage. Available pharmacokinetic data derived from studies of drugs that are largely dependent on a single CYP pathway for their elimination provide initial assessments of the developmental profile of that particular CYP isoform. Essentially then, pharmacogenetics in a pediatric context refers to the changes in phenotype that occur as a child grows and develops. Furthermore, the apparent drug biotransformation "phenotype" may be influenced by disease (infection), environmental factors (diet and environmental contaminants) and concurrent medications; however, drug response is a function of the complex interplay among genes involved in drug transport, drug biotransformation, receptors, and signal transduction processes, among others. Therefore, optimization of pediatric pharmacotherapy necessarily requires that developmental changes in each of these areas and not just drug biotransformation be investigated thoroughly before the promise of pharmacogenetics and pharmacogenomics for rational therapeutics can be realized in children.