Tuesday, November 10, 2020
In the sections pharmacogenomic mechanisms, pharmacogenomic evidence and guidelines for psychiatry, and pharmacogenomic testing in psychiatry the review provides an up-to-date summary of recent developments that clinicians should know when considering PGx testing for their patients. It summarizes and discusses the evidence that was considered by the International Society of Psychiatric Genetics (ISPG) for a statement about “Genetic testing and psychiatric disorders” updated in 2019.
The author group concludes that PGx testing should be viewed as part of the decision supporting measures to assist implementation of good clinical care, highlighting CYP2D6, CYP2C19, HLA-A, and HLA-B. For further details read the review [PMID: 33147643].
Thursday, November 5, 2020
Clinical Pharmacogenetics Implementation Consortium (CPIC) has released the first version of its database and API to the public. The CPIC database is a relational database containing data from CPIC's guidelines in structured formats. These data include the guideline manuscript recommendations and information from all of the supporting guideline tables, including gene variant and allele frequencies, function assignments, definitions, diplotype-phenotype mappings and example CDS (clinical decision support) language, as well as example drug-based pre- and post-test alerts and CDS flow charts. Mappings of CPIC gene and drug names to multiple vocabularies/terminologies are also available. The CPIC database can be accessed through the CPIC API or via whole database exports. The API is a RESTful interface and allows access to all parts of the currently defined data model. Documentation for how to use the API with examples can be found in the database documentation. Versioned, whole-database exports can be found in each release on GitHub.
We encourage users to please read the extensive documentation about the data models and formats. Different guideline gene-drug pairs require slightly different models which is explained in the documentation. An understanding of these differences is critical to use the data appropriately. Additionally, each guideline has unique caveats and nuances that can only be fully appreciated by reading the guideline itself, so we encourage users to read the guidelines when accessing and using data from the CPIC database.
We anticipate and encourage user feedback from the community. Please contact us at firstname.lastname@example.org with questions and comments.
Thursday, October 1, 2020
Tuesday, September 29, 2020
The PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19 is now published in Clinical Pharmacology and Therapeutics.
The article is the first in a series of Pharmacogenomics Knowledgebase (PharmGKB) tuto
Using examples of drugs found in the portal the authors demonstrate some of the main features of PharmGKB including guideline, drug label, clinical, and variant annotations.
Wednesday, September 23, 2020
The co-PIs of the Pharmacogenomics Clinical Annotation Tool (PharmCAT). Dr. Marylyn Ritchie of the University of Pennsylvania and Dr. Teri Klein of Stanford University were awarded a three year grant from the National Institutes of Health National Human Genome Research Institute (NIH NHGRI) to continue and expand the project. PharmCAT was originally created in 2016 and is a tool that: (1) extracts variants found in CPIC guideline genes from a sequencing or genotyping Variant Call Format (VCF) file, (2) assigns star alleles, diplotypes and drug phenotypes based on slightly modified PharmVar core alleles in CPIC/PharmGKB definition tables and CPIC allele function and phenotype tables, and (3) provides an HTML/PDF report including CPIC genotype-based drug prescribing recommendations.
We published the initial assessment of PharmCAT in Clinical Pharmacology and Therapeutics in 2019 (PMID: 31306493) and the beta version is currently available for testing. Due to limited resources, PharmCAT has only been tested on a small sample of genotype data and with information from CPIC guidelines as of 2018. The new funding will enable PharmCAT to (1) update to current CPIC guidelines and release version 1.0, (2) create a module for VCF pre-processing and quality control, (3) export an electronic health record (EHR) compatible report using Fast Healthcare Interoperability Resources (FHIR) specifications, and (4) provide the ability to run multiple VCF files at one time (batch processing). We will announce the PharmCAT v.1.0 release on the PharmGKB blog. Check the PharmCAT website to see updates as they happen.
This work is supported by the NIH NHGRI U24HG010862.
PharmCAT workflow below. Yellow boxes are input files for PharmCAT. Blue boxes are PharmCAT modules. Green boxes are PharmCAT module output and input into the next module. Grey boxes are alternate input into PharmCAT.
Tuesday, September 8, 2020
The 2020 CPIC Guideline update for HLA-B, CYP2C19 and phenytoin dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for phenytoin and on the CPIC website.
Phenytoin is an antiepileptic drug with inter-individual pharmacokinetic variability, partly due to CYP2C9 genetic variation, and a narrow therapeutic index. The presence of the HLA-B*15:02 variant allele is associated with an increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis.
Literature published after the 2014 guideline was reviewed and the recommendations and supplemental information were updated. This includes updates to CYP2C9 allele assignments using the activity score (AS) system. The CYP2C9*2/*2 diplotype (AS=1) is now translated into the IM phenotype group (originally translated to PM). This is based on similar effects of CYP2C9*1/*3 (AS=1) and CYP2C9*2/*2 on metabolic ratio and dose requirements for multiple substrates. CYP2C9*3 is classified as ‘no function’ allele with an activity value of 0 for AS calculation.
For therapeutic recommendations and further details including an algorithm for suggested clinical actions based on HLA-B*15:02 and CYP2C9 genotype, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update.
Wednesday, August 26, 2020
PharmGKB and CPIC have formalized a partnership with ClinGen to bring pharmacogenomics (PGx) expertise to the primarily disease-focused, NIH-funded mega-resource. ClinGen's goals include defining the clinical relevance of genes and variants for use in precision medicine and research and disseminating that knowledge to the broader community. They have developed and implemented data standards for clinical annotation and interpretation of genes and variants. To date, this annotation and interpretation has focused on disease-related genes and variants. The partnership with PharmGKB and CPIC was established to bring PGx knowledge to the ClinGen community. Gene-level PGx entries which link to PharmGKB and CPIC will be added to the current validation, dosage and actionability curations displayed on ClinGen so that users will be able to access the PharmGKB and CPIC resources through the ClinGen interface. Planning is underway for the PGx display. Additionally, PharmGKB is working to provide links back to ClinGen for genes and variants associated with disease phenotypes.
Tuesday, August 11, 2020
The CPIC Guideline for CYP2C19 and proton pump inhibitor (PPI) dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for omeprazole, lansoprazole, pantoprazole, dexlansoprazole, and on the CPIC website.
PPIs inhibit the final pathway of acid production, which leads to inhibition of gastric acid secretion. PPIs are widely used in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. The first-generation inhibitors omeprazole, lansoprazole and pantoprazole are extensively metabolized by the cytochrome P450 isoform CYP2C19 and to a lesser extent by CYP3A4. The second-generation PPI dexlansoprazole appears to share a similar metabolic pathway to lansoprazole. CYP2C19 genotypes have been linked to PPI exposure and in turn to PPI efficacy and adverse effects.
The CPIC guideline summarizes evidence from the literature and provides therapeutic recommendations for omeprazole, lansoprazole, pantoprazole, dexlansoprazole based on CYP2C19 genotype. For therapeutic recommendations and further details, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing.
Monday, August 10, 2020
PharmVar and PharmGKB are excited to announce that CYP3A5 has been transitioned into the PharmVar database. Variation information has been extensively curated by the PharmVar CYP3A5 gene experts which led to the correction of some allele definitions or reclassification of others. The submission of new data added novel suballeles, as well as helped to raise the evidence levels for several alleles from ‘Lim’ to ‘Def’. Important CYP3A5 information is provided in the ‘Read Me’ document such as reference sequences used and how the PharmVar CAVE tool facilitates comparisons of core allele definitions. All changes and revisions have been summarized in the ‘Change Log’ document. Here we also list all new haplotypes. Check it out at https://www.pharmvar.org/gene/CYP3A5.
And finally, a big thank you to all of the CYP3A5 gene experts who serve on this panel for their hard work.
Thursday, July 30, 2020
Friday, July 10, 2020
ICPC publishes GWAS analysis on platelet reactivity and cardiovascular response in patients treated with clopidogrel
- Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC). Clin Pharmacol Ther. 2020 May 30. doi: 10.1002/cpt.1911. PMID: 32472697
- Pharmacogenomic Polygenic Response Score Predicts Ischemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients. Eur Heart J Cardiovasc Pharmacother. 2019 Sep 3:pvz045. doi:10.1093/ehjcvp/pvz045. PMID: 31504375.
- Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J. 2018 Apr;198:152-159. doi: 10.1016/j.ahj.2017.12.010. PMID: 29653637
Monday, July 6, 2020
Thursday, June 11, 2020
The Centers for Medicare and Medicaid Services (CMS) have posted a FUTURE Local Coverage Determination (LCD) for MolDX: Pharmacogenomics Testing (L38294). This includes broad coverage for pharmacogenomic testing to go in effect this summer.
CPIC provided presentations to Palmetto prior to their draft LCD, and provided written comments on LCD ID L38294 back in November of 2019. CPIC members were instrumental in the feedback provided, and many of CPIC’s suggestions have been incorporated, and CPIC guidelines are cited throughout their document. For example, their post states: “PGx tests are indicated when medications are being considered for use (or already being administered) that are medically necessary, appropriate, and approved for use in the patient’s condition and are known to have a gene(s)-drug interaction that has been demonstrated to be clinically actionable as defined by the FDA (PGx information required for safe drug administration) or Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines (category A and B).”
The LCD defines ‘actionable use’ of PGx as “when the genotype information may lead to selection of or avoidance of a specific therapy or modification of dosage of a therapy. The selection, avoidance, or dose change must be based on the FDA-label for the drug, an FDA warning or safety concern, or a CPIC level A or B gene-drug interaction”. PharmGKB uses the ‘Alternate Drug’ and ‘Dosing Info’ tags to highlight drug label annotations where the label contains information about contraindications or dosing changes based on genotype information. These tags can be used to filter our table of drug label annotations.
Monday, June 8, 2020
On behalf of all of the NIH PGRN funded investigators, we thank NIH for their past support, particularly our original program officer, Dr. Rochelle Long (NIGMS Director, Division of Pharmacology, Physiology and Biological Chemistry).
Update 6/29/2020 The inaugural Research In Progress (RIPS) webinar from the PGRN society will be given by Alan Shuldiner, MD, on Friday July 17 at 11am Eastern time. Dr. Shuldiner will speak on "Building bridges between industry, academia, health care systems and communities to advance Precision Medicine".
From Friday August 14, RIPS webinars will be held on the second Friday of every month at 11am Eastern time for all PGRN members. A schedule of upcoming RIPS webinars can be found here. If you are interested in joining the PGRN, you can become a member at www.pgrn.org.
Friday, May 29, 2020
Tuesday, May 26, 2020
Monday, May 18, 2020
Friday, May 1, 2020
Dr. Caudle has been the CPIC Coordinator/Director for CPIC for 8 years. During this time she has overseen the CPIC guideline development for 22 CPIC guidelines and 13 guideline updates and has led several CPIC projects. We thank Dr. Mary Relling for her outstanding leadership and we are thrilled that she continue her involvement in CPIC as a co-Investigator at SJRCH.
Congratulations, Dr. Caudle!
Wednesday, April 29, 2020
• Reduced registration fees for PGRN meetings and workshops, including member receptions and poster sessions at annual meetings with large scientific societies such as ASHG and ASCPT
• Participation in member calls/webinars and Research in Progress Seminars
• Membership on PGRN program committees for meetings and workshops
• Network with colleagues and establish collaborations
• Leadership opportunities for members (e.g., serve on PGRN committees, board, and as leaders)
• Awards for trainees and mentorship opportunities
• Access to PGRN web pages highlighting pharmacogenomics tools and resources, events and other useful information for PGx research, education and clinical practice
Friday, April 17, 2020
Following a drug link on the PharmGKB COVID-19 webpage takes the user to PharmGKB annotations about that drug, including FDA-approved drug labels, variant and clinical annotations based on peer-reviewed literature and pharmacokinetic and/or pharmacodynamic pathways. This resource is under development. The COVID-19 space is changing rapidly and new clinical trials continue to be added for investigational drugs, some of which are being repurposed and some of which are experimental with very limited information. We will update the PharmGKB webpage as we get new information.
Monday, April 13, 2020
Wednesday, March 25, 2020
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are among the most commonly prescribed drugs to treat pain and inflammation. The main therapeutic effect of NSAIDs occurs via inhibition of prostaglandin biosynthesis mediated by the cyclooxygenases (COXs). Most NSAIDs are reversible inhibitors of both the COX-1 and COX-2 isoforms. Celecoxib, meloxicam, and diclofenac are selective inhibitors of COX-2. Hepatic metabolism by cytochrome P450 isoforms CYP2C9, 1A2, and 3A4, and renal excretion are the principal routes of clearance of the majority of NSAIDs. Genetic variants in CYP2C9 (eg. CYP2C9*2 and *3), along with other genetics and clinical factors, have been shown to affect systemic plasma concentrations of NSAIDs and potentially safety. Patients with CYP2C9 decreased or no function alleles may have elevated exposure and at increased risk for adverse effects.
The CPIC guideline summarizes evidence from the literature and provides therapeutic recommendations for a number of NSAIDs (celecoxib, flurbiprofen, ibuprofen, lornoxicam, meloxicam, piroxicam and tenoxicam) based on CYP2C9 genotype. For therapeutic recommendations and further details, please refer to the CPIC Guideline for CYP2C9 and Nonsteroidal Anti-inflammatory Drugs (NSAIDs).