Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium (vol 101, pg 341, 2017)
01 Jul 2017-
TL;DR: Pre‐emptive genotyping of a panel of clinically relevant PGx‐markers will be implemented across healthcare institutions in seven European countries, and the impact on patient outcomes and cost‐effectiveness will be investigated.
About: The article was published on 2017-07-01 and is currently open access. It has received 167 citations till now. The article focuses on the topics: Pharmacogenomics.
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TL;DR: The aim of this paper is to compare both initiatives and explore differences between the published guidelines, with the objective to achieve harmonization.
Abstract: Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well-known gene-drug pairs. Published recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization.
186 citations
01 Nov 2017
TL;DR: The origins and development of pharmacogenomics are surveyed; some of the challenges associated with the clinical implementation of pharmacagenomics are addressed; and future advances in this important genomic discipline are attempted to foresee.
Abstract: Pharmacogenomics is the use of genomic and other "omic" information to individualize drug selection and drug use to avoid adverse drug reactions and to maximize drug efficacy. The science underlying pharmacogenomics has evolved rapidly over the 50 years since it was first suggested that genetics might influence drug response phenotypes. That process has occurred in parallel with advances in DNA sequencing and other molecular technologies, with striking increases in our understanding of the human genome. There are now many validated examples of the clinical utility of pharmacogenomics, and this type of clinical genomic information is increasingly being generated in clinical laboratories, incorporated into electronic health records, and used to "tailor" or individualize drug therapy. This review will survey the origins and development of pharmacogenomics; it will address some of the challenges associated with the clinical implementation of pharmacogenomics; and it will attempt to foresee future advances in this important genomic discipline, one that almost certainly will be among the earliest and most widely adopted aspects of clinical genomics.
155 citations
TL;DR: Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.
Abstract: Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.
122 citations
Cites background from "Implementing Pharmacogenomics in Eu..."
...For patients starting SVT (or ATV) with at least one SLCO1B1 rs4149056 minor allele, the DPWG recommendations are provided to them and their healthcare team [274]....
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...The implementation of SLCO1B1 rs4149056 testing [274] may help improve predictive power....
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...It is also noteworthy that a large multicentre implementation initiative is pre-emptively genotyping patients starting one of 39 drugs for over 45 pharmacogenomic variants, and prospectively determining the incidence of ADRs compared to standard care [274]....
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TL;DR: This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.
Abstract: The field of pharmacogenomics (PGx) is gradually shifting from the reactive testing of single genes toward the proactive testing of multiple genes to improve treatment outcomes, reduce adverse events, and decrease the burden of unnecessary costs for healthcare systems. Despite the progress in the field of pharmacogenomics, its implementation into routine care has been slow due to several barriers. However, in recent years, the number of studies on the implementation of PGx has increased, all providing a wealth of knowledge on different solutions for overcoming the obstacles that have been emphasized over the past years. This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.
111 citations
Cites methods from "Implementing Pharmacogenomics in Eu..."
...U-PGx (Ubiquitous Pharmacogenomics) Implement PGx through a pre-emptive panel strategy; studies of the impact on patient outcomes and cost-effectiveness; exploratory analysis to understand PGx [17] Krebs and Milani Human Genomics (2019) 13:39 Page 4 of 13...
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...U-PGx has developed an e-learning platform for distributing general PGx knowledge suitable for physicians and pharmacists [17]....
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TL;DR: It is concluded that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology.
Abstract: Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drug-metabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.
101 citations
Cites background from "Implementing Pharmacogenomics in Eu..."
...eu/) that a ims to implement and evaluate the impact of pharmacogenomic testing on therapeutic outcomes in seven European clinical centers [134]....
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References
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TL;DR: HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir and showed that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug.
Abstract: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. Methods This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701–positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. Results The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). Conclusions HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
1,594 citations
"Implementing Pharmacogenomics in Eu..." refers background in this paper
...Several randomized controlled trials have provided gold-standard evidence for the clinical utility of single drug-gene PGx tests to: (1) guide dosing for warfarin,(8,9) acenocoumarol, phencopromon,(10) and thiopurines(11); and (2) guide the drug selection of abacavir.(12) Additionally, several prospective cohort studies have been performed indicating the clinical utility of single drug-gene PGx tests to guide drug selection of carbamazepine(13) and allopurinol....
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1,073 citations
"Implementing Pharmacogenomics in Eu..." refers background in this paper
...It promises to personalize medicine by using an individual’s genetic makeup, which predicts drug response, to guide optimal drug and dose selection.(3,4) This removes the traditional “trial and error” approach of drug...
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TL;DR: Recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP3A5, and HLA‐B*5701, and factor V Leiden (FVL).
Abstract: Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).
877 citations
TL;DR: A vision for the future of genomics research is articulated and the path towards an era of genomic medicine is described, as advances in genomics are harnessed to obtain robust foundational knowledge about the structure and function of the human genome.
Abstract: There has been much progress in genomics in the ten years since a draft sequence of the human genome was published. Opportunities for understanding health and disease are now unprecedented, as advances in genomics are harnessed to obtain robust foundational knowledge about the structure and function of the human genome and about the genetic contributions to human health and disease. Here we articulate a 2011 vision for the future of genomics research and describe the path towards an era of genomic medicine.
860 citations
TL;DR: The slow rate at which pharmacogenetic tests are being adopted in clinical practice is partly due to the lack of specific guidelines on how to adjust medications on the basis of the genetic test results.
Abstract: The slow rate at which pharmacogenetic tests are being adopted in clinical practice is partly due to the lack of specific guidelines on how to adjust medications on the basis of the genetic test results. One of the goals of the Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health’s Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) is to provide peer-reviewed, updated, evidence-based, freely accessible guidelines for gene/drug pairs. These guidelines will facilitate the translation of pharmacogenomic knowledge from bench to bedside.
848 citations