Pharmacogenetic information in Swiss drug labels - a systematic analysis.

Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as "actionable PGx". Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group "nervous system". Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group.

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.

New Pharmacogenomics Research Network: An Open Community Catalyzing Research and Translation in Precision Medicine.

The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.

Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

Novel Disease-Drug Database Demonstrating Applicability for Pharmacogenomic-Based Prescribing.

Significant advances have been made in the clinical implementation of pharmacogenomics in recent years with tools for clinical decision support (CDS) being developed and integrated in the electronic health record (EHR). In this issue, the article by Hussain et al. describes the creation of a disease-drug association tool that enables providers to search by disease indications to receive a list of treatment options marked with pharmacogenomics annotations at the point of prescribing.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing.

The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing.

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Enabling the curation of your pharmacogenetic study.

As pharmacogenomics becomes integrated into clinical practice, curation of published studies becomes increasingly important. At the Pharmacogenomics Knowledgebase (PharmGKB; www.pharmgkb.org), pharmacogenetic associations reported in published articles are manually curated and evaluated. Standard terminologies are used, making findings uniform and unambiguous. Lack of information, clarity, or standards in the original report can make it difficult or impossible to curate. We provide 10 rules to help authors ensure that their results are accurately captured and integrated.

Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing.

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA-B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA-B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost-effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.