Pharmacoeconomic evaluation of warfarin pharmacogenomics

INTRODUCTION: the merit of applying pharmacogenomics in the induction phase of warfarin therapy for personalized dosing is controversial and highly dependent on its cost-effectiveness. AREAS COVERED: published studies on pharmacoeconomics of warfarin pharmacogenomic application are reviewed. A literature search was done using Medline and Embase covering the period 2000 - 2010. Decision tree and Markov modeling were the most frequently used methods in the reviewed reports. Studies incorporating clinical efficacy data of genotype-guided dosing algorithm had shown that warfarin pharmacogenomics would improve quality-adjusted life-years (QALYs) gained. Nevertheless, it was unlikely to be cost-effective for general patients. Influential factors to improve the cost-effectiveness included low genotyping cost, high effectiveness in improving anticoagulation control/event rate, and applying warfarin pharmacogenomics to patients with high bleeding risk or at practice sites with suboptimal management of anticoagulation control. EXPERT OPINION: warfarin pharmacogenomics would improve QALYs and could possibly be cost-effective in selected patient groups or practice sites.     

Clinical pharmacogenomics of warfarin and clopidogrel

Genetic polymorphisms significantly influence responses to warfarin and clopidogrel. Polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase genes change warfarin pharmacokinetics and pharmacodynamics, respectively. Because these polymorphisms influence warfarin dose requirements, they may primarily help determine therapeutic warfarin doses in patients who newly start on the drug. To assist in estimating therapeutic warfarin doses, the warfarin label provides a pharmacogenomic dosing table and various warfarin pharmacogenomic dosing algorithms are available. On the other hand, polymorphisms in the CYP2C19 gene affect clopidogrel pharmacokinetics. These polymorphisms may be useful to identify clopidogrel nonresponders who may benefit from taking an alternative antiplatelet agent such as prasugrel and ticagrelor. Although both drugs have pharmacogenomic tests available for clinical use, their clinical utilities have not been established and are currently being actively studied. In this review, clinical application of warfarin and clopidogrel pharmacogenomics will be focused. With the current level of evidence, potential patients who may get benefit from warfarin and clopidogrel pharmacogenomic testing will be discussed. In addition, the interpretation of the warfarin and clopidogrel test results and the current barriers to widespread use of warfarin and clopidogrel pharmacogenomic testing will be discussed.     

Clinical applicability of sequence variations in genes related to drug metabolism

The Human Genome and the Hap Map Projects as well as the extensive use of deep resequencing worldwide, have contributed to a massive catalogue of reported single nucleotide polymorphisms (SNPs) and other genetic variations in the human genome. Pharmacogenomics is an emerging field that combines genetics with pharmacokinetics and pharmacodynamics of the drug in attempt to understand inter-individual differences among patients and develop more accurate drug dosing. However, only for the minority of those variations an association with phenotype has been established. Here, we provide an overview of genes and genetic variants that influence inter-individual dosing of three of the most widely used drugs, namely warfarin, irinotecan and thiopurine drugs, to highlight a tangible benefit of translating genomic knowledge into clinical practice. Therefore, particular SNPs in vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1) and thiopurine S-methyltransferase (TPMT) genes has proven to be applicable for optimising the dosage in pursuit of maximum efficacy and minimum adverse effects. Thus, they set an important paradigm of implementation of pharmacogenomics in the mainstream clinical practice.     

Relevance of pharmacogenomics for developing countries in Europe

Pharmacogenomics holds promise of personalized treatment for patients suffering from many common diseases, particularly those with multiple treatment modalities. Owing to recent advances in the deciphering of the human genome sequence, high throughput genotyping technology has led to the reduction of the overall costs of genetic testing and allowed the inclusion of genotype-related dosing recommendations into drug package inserts, hence enabling the integration of pharmacogenomics into clinical practice. Although pharmacogenomics gradually assumes an important part in routine clinical practice in developed countries, many countries, particularly from the developing world, still do not have access either to the knowledge or the resources to individualize drug therapy. The PharmacoGenetics for Every Nation Initiative (PGENI) aims to fill this gap, by making pharmacogenomics globally applicable, not only by defining population-specific pharmacogenomic marker frequency profiles but also by formulating country-specific recommendations for drug efficacy and safety. This article aims to highlight the PGENI activities in Europe in an effort to make pharmacogenomics readily applicable in the European healthcare systems, particularly those in developing countries.     

Pharmacogenomics – how close/far are we to practising individualized medicine for children?

The translation of pharmacogenomics into clinical practice is a key approach for practising individualized medicine, which aims to maximize drug efficacy and minimize drug toxicity. Since the completion of both the Human Genome Project and the International HapMap project, the development of pharmacogenomics has been greatly facilitated. However, progress in translating pharmacogenomics into clinical practice, especially in paediatric medicine, is unexpectedly slow. Many challenges from different areas remain. This paper discusses the existing applications and the limitations to the implementation of paediatric pharmacogenomics, as well as possible solutions for overcoming these limitations and challenges.     

华法林药物基因组学的研究推动其个体化医疗的进程

药物基因组学可以帮助人们更好地认识药物与机体之间的相互作用。华法林是临床上广泛使用的香豆素类口服抗凝血药,其狭窄的抗凝治疗指数范围和抗凝不当所致的并发症一直困扰着临床医师,如何合理使用已经成为一个难题。近年来,随着药物基因组学的快速发展,研究发现药动学和药效学多个相关基因的多态性造成了个体差异,影响了华法林的使用剂量。本文综述了药物基因组学研究在华法林用药中的国内外最新进展,为华法林个体化医疗提供参考依据。     

Pharmacogenomics research and its clinical implementation in Thailand: Lessons learned from the resource-limited settings

Several barriers present challenges to implementing pharmacogenomics into practice. This review will provide an overview of the current pharmacogenomics practices and research in Thailand, address the challenges and lessons learned from delivering clinical pharmacogenomic services in Thailand, emphasize the pharmacogenomics implementation issues that must be overcome, and identify current pharmacogenomic initiatives and plans to facilitate clinical implementation of pharmacogenomics in Thailand. Ever since the pharmacogenomics research began in 2004 in Thailand, a multitude of pharmacogenomics variants associated with drug responses have been identified in the Thai population, such as HLA-B115:02 for carbamazepine and oxcarbazepine, HLA-B158:01 for allopurinol, HLA-B113:01 for dapsone and cotrimoxazole, CYP2B6 variants for efavirenz, CYP2C913 for phenytoin and warfarin, CYP3A513 for tacrolimus, and UGT1A116 and UGT1A1128 for irinotecan, etc. The future of pharmacogenomics guided therapy in clinical settings across Thailand appears promising because of the availability of evidence of clinical validity of the pharmacogenomics testing and support for reimbursement of pharmacogenomics testing.     

Role of pharmacogenomics in the management of traditional and novel oral anticoagulants

Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration-cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotypeguided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available.     

Preparing for the revolution--pharmacogenomics and the clinical lab

Pharmacogenomics seeks to apply the field of genomics to improve the efficacy and safety of therapeutics. Sinmply put, pharmacogenomics is genetic-based testing to determine patient therapy. Interestingly, the clinical lab has rarely been discussed within the context of pharmacogenomics. Since clinical labs fill a key role in drug development it is important that they are included in pharmacogenomic discussions. Currently, clinical labs assist pharmaceutical sponsors in preclinical pharmacogenetic testing. In the future, clinical labs will be looked to for genetic test development and validation, and high-throughput genotyping of patients in clinical trials and routine testing. Clinical labs are an essential link in the chain of pharmacogenomic drug development, a fact which must be recognised by both the labs themselves and the industry as a whole.     

Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective

Pharmacogenomics and pharmacogenetics provide methodologies that can lead to DNA-based tests to improve drug selection, identify optimal dosing, maximize drug efficacy or minimize the risk of toxicity. Rapid advances in basic research have identified many opportunities for the development of 'personalized' treatments for individuals and/or subsets of patients defined by genetic and/or genomic tests. However, the integration of these tests into routine clinical practice remains a major multidisciplinary challenge, and even for well-established biomarkers there has been little progress. Here, we consider this challenge from a regulatory perspective, highlighting recent initiatives from the FDA that aim to facilitate the integration of pharmacogenetics and pharmacogenomics into drug development and clinical practice.     

Identifying the genotype behind the phenotype: a role model found in VKORC1 and its association with warfarin dosing

Genotype-phenotype studies in pharmacogenomics promise to identify the genetic factors that contribute substantially to variation in individual drug response. While most genetic association studies have failed to deliver this promise, several recent examples serve as a reminder that these associations do exist and can be identified when investigated using well-designed studies. Here, we describe the path taken to identify the association between common vitamin K epoxide reductase complex subunit 1 genetic variation and warfarin dosing in patients. We also describe the key elements that led the way, such as definition of the phenotype, confirmation of a genetic component, determination of biological plausibility and selection of genetic polymorphisms. We also describe several avenues that are yet to be explored for the specific vitamin K epoxide reductase complex subunit 1 warfarin example that can also be generalized as future directions for many genetic association studies in pharmacogenomics. These future avenues will be best explored using diverse approaches encompassing clinical, statistical and genomic methods currently being developed for genotype-phenotype studies in human populations.     

HIV resistance testing in the USA--a model for the application of pharmacogenomics in the clinical setting

Although there is debate about how and when the medical community will readily adopt pharmacogenomics into clinical practice, HIV genotyping has become an integral part of AIDS patient management in the USA since 1996. Genotyping for HIV-1 drug resistance serves as a paradigm for the way pharmacogenomics is likely to be introduced into patient care. This review discusses the unique role that HIV-1 genotype testing plays in identifying resistance in patients and how that information is used to modify therapy selection and impact the progression of disease. In addition, the important issues relating to reimbursement and the cost-effectiveness of genotyping are also discussed.     

Pharmacogenetics, Pharmacogenomics, and Cardiovascular Therapeutics

The completion of sequencing of the human genome will be the vanguard for numerous advances in medicine. The first discernible application is likely to occur in pharmacogenomics, a field focused on the influence of genetic differences on the variability in patients’ response to medications. While an inherited basis for drug response has been recognized for some time, it is the confluence of molecular biology, high-throughput genotyping, and bioinformatics that has made it practical to study the genetic basis of variability to medications on a large scale. Pharmacogenomics may enable clinicians to prospectively identify patients most likely to derive benefit from a drug, with minimal likelihood of adverse events. This DNA-based approach to predicting clinical drug efficacy and toxicity would shift the current prescribing paradigm from its empirical nature to a more patient-specific model, ushering in a new era of personalized medicine. Polymorphisms in drug metabolizing enzymes, drug targets, and disease pathogenesis genes are associated with therapeutic effect to cardiovascular pharmacotherapy. Moreover, pharmacogenomics and functional genomics are expected to have a profound impact on the process of drug discovery and development. Finally, pharmacogenomics is likely to transform the way clinical trials are conducted by allowing for the selection of a more homogeneous study population, thereby reducing the size and cost of clinical investigation.     

Pharmacogenomics of cardiovascular drugs and adverse effects in pediatrics

Individual response to medication is highly variable. For many drugs, a substantial proportion of patients show suboptimal response at standard doses, whereas others experience adverse drug reactions (ADRs). Pharmacogenomics aims to identify genetic factors underlying this variability in drug response, providing solutions to improve drug efficacy and safety. We review recent advances in pharmacogenomics of cardiovascular drugs and cardiovascular ADRs, including warfarin, clopidogrel, β-blockers, renin-angiotensin-aldosterone system inhibitors, drug-induced long QT syndrome, and anthracycline-induced cardiotoxicity. We particularly focus on the applicability of pharmacogenomic findings to pediatric patients in whom developmental changes in body size and organ function may affect drug pharmacokinetics and pharmacodynamics. Solid evidence supports the importance of gene variants in CYP2C9 and VKORC1 for warfarin dosing and in CYP2C19 for clopidogrel response in adult patients. For the other cardiovascular drugs or cardiovascular ADRs, further studies are needed to replicate or clarify genetic associations before considering uptake of pharmacogenetic testing in clinical practice. With the exception of warfarin and anthracycline-induced cardiotoxicity, there is lack of pharmacogenomic studies on cardiovascular drug response or ADRs aimed specifically at children or adolescents. The first pediatric warfarin pharmacogenomic study indeed indicates differences from adults, pointing out the importance and need for pediatric-focused pharmacogenomic studies.     

4th Annual Pharmacogenomics and Medicine Lectures

In the future, pharmacogenomics will play an important role in the treatment of patients by making it possible to predict drug response based on an individual's genetic make-up. Similarly, pharmacogenomics may be used to reduce the probability that adverse effects will occur. The use of a patient's genetic information will lead to greater predictability in clinical outcomes and personalisation of medical care. Pharmacogenomic information can also aid in drug development by helping to select individuals that are likely to respond to a medication for participation in clinical trials. Integration of pharmacogenomics into the healthcare system has a number of potential economic benefits, including reduced costs of healthcare and drug discovery. The FDA has no specific plans to regulate therapy-guiding pharmacogenomic tests, which are different from diagnostic genetic tests. There are a number of ethical issues related to pharmacogenomics, including the credibility of the system for protecting the rights and welfare of human research subjects, general concerns about genetic research, privacy issues and equitable distribution of the technology. To ensure integration of pharmacogenomics into the healthcare system it will be important to obtain public support through education about the benefits and risks of this technology.     

Pharmacogenomics: bench to bedside

Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. Since its origins in the mid-twentieth century, a major driving force in pharmacogenetics research has been the promise of individualized drug therapy to maximize drug efficacy and minimize drug toxicity. In recent years, the convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics, and led to increasing enthusiasm for the 'translation' of this evolving discipline into clinical practice. Here, we briefly summarize the development of pharmacogenetics and pharmacogenomics, and then discuss the key factors that have had an influence on - and will continue to affect - the translation of pharmacogenomics from the research bench to the bedside, highlighting the challenges that need to be addressed to achieve this goal.     

Methodological and statistical issues in pharmacogenomics

Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA‐B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S‐methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies. In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome‐wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways.     

Clinical pharmacogenomics: applications in pharmaceutical R&D

Within the pharmaceutical industry, the application of clinical pharmacogenomics promises to enhance the discovery of drug response markers, reduce the size and expense of clinical drug trials and provide a new tool for addressing regulatory approval issues. Today, pharmacogenomics is primarily applied early in clinical drug development by prospective genotyping in Phase I trials, to ensure that a subject population is representative with respect to drug metabolism phenotypes. The banking of genetic material from later stage trials for retrospective studies on drug response is becoming more frequent, but is not yet standard in the industry. This article provides an overview of the driving forces that are encouraging pharmacogenomic strategy development in the pharmaceutical industry, and the significance of polymorphisms in drug metabolizing enzymes (DMEs) and target proteins.