Review and Consensus on Pharmacogenomic Testing in Psychiatry published in Pharmacopsychiatry

Review and Consensus on Pharmacogenomic (PGx) Testing in Psychiatry was recently published in the journal Pharmacopsychiatry [PMID: 33147643].

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].

CPIC releases the CPIC database v.1.0

 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 contact@cpicpgx.org with questions and comments.

CPIC releases updated Genes-Drugs list

Clinical Pharmacogenetics Implementation Consortium (CPIC) has posted an updated Genes-Drug list. Changes include: 

1. A new column was added to the table called “CPIC Level Status”. Assigned CPIC levels have always been considered provisional unless and until the gene/drug pair has been reviewed in the course of a CPIC guideline. All gene-drug pairs reviewed as part of CPIC guidelines have been assigned a “final” assignment; others were assigned “provisional,” and this column designation should clarify this distinction for the user. 

2. CPIC Levels “A/B”, “B/C” and “C/D” have been included in the past, but now these levels have been defined at https://cpicpgx.org/prioritization/#leveldef. 

3. Gene/drug pairs (including some in the FDA’s new PGx association list) were re-evaluated. Some gene-drug pairs were added and some had their provisional levels changed after preliminary review of the evidence and actionability recommended by others. 

4. The previous version of the list contained some drug classes. In this list the drugs have been separated out individually so that classes are no longer listed. 

5. Some gene-drug pairs were removed because on reassessment, they did not meet the criteria for inclusion.

PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19

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) tutorials intended as a resource to help users become quickly acquainted with the wealth of information stored in PharmGKB. 

Each article will center around a specific topic, like in this publication the PharmGKB COVID-19 portal (previously blogged about it here). 

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.

PharmCAT grant awarded

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.

CPIC Guideline update: HLA-B/CYP2C9 and Phenytoin/Fosphenytoin

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.

PharmGKB and CPIC Partner with ClinGen

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.

New CPIC Guideline: CYP2C19 and Proton Pump Inhibitors (PPIs)

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.

CYP3A5 released on PharmVar

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.

PharmVar user survey released

The Pharmacogene Variation (PharmVar) Consortium, a central repository for pharmacogene (PGx) variation that focuses on haplotype structure and allelic variation is interested in hearing from the PGx user community regarding their resource.  Please take a couple of minutes to fill out their user survey.

ICPC publishes GWAS analysis on platelet reactivity and cardiovascular response in patients treated with clopidogrel

The GWAS analysis on platelet reactivity and cardiovascular outcome for clopidogrel, the third paper by the International Clopidogrel Pharmacogenomics Consortium (ICPC), has just been published in journal Clinical Pharmacology & Therapeutics.

Clopidogrel is an antiplatelet agent widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Individual responses to clopidogrel show substantial variability, and poor response is often associated with adverse cardiovascular outcomes. Genetic variants in CYP2C19 play an important role in response to clopidogrel. However, loss of function variants in CYP2C19 only account for a small percentage of the overall variation in platelet reactivity, suggesting that novel genetic variants for clopidogrel response remain to be discovered.

The International Clopidogrel Pharmacogenomics Consortium (ICPC) was established to identify genetic factors influencing clopidogrel efficacy and cardiovascular outcomes, using both genome-wide and candidate gene approaches. It comprises 17 study sites from 13 countries that contributed clinical and genetic data for a total of 8,929 patients treated with clopidogrel. Investigators from ICPC performed a GWAS on data from 2,750 individuals of European ancestry. The GWAS analysis showed that CYP2C19*2 is still the strongest genetic determinant of on-clopidogrel platelet reactivity, and no SNP reached genome wide significance for major adverse cardiovascular events (MACE) endpoints. However, in subgroup analyses for patients with coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance with MACE or stent thrombosis outcomes. This study represents the largest GWAS performed to date for clopidogrel response.

In addition to the GWAS analysis, the ICPC previously published the design paper and results from the candidate gene study, which developed a pharmacogenomic polygenic response score (PgxRS) - based on 31 candidate gene polymorphisms and assessed in 3,391 clopidogrel treated patients from the ICPC.  Several variants in CYP2C19, CES1, CYP2C9, CYP2B6 and PEAR1 were identified to have significantly influenced on-clopidogrel platelet reactivity. Patients who carried increasing number of risk alleles that lead to high platelet reactivity were significantly more likely to experience adverse cardiovascular events than patients who carried alleles that lead to better platelet inhibition.

For more information, please refer to the following publications by ICPC:

1. 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
2. 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.
3. 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

PharmVar GeneFocus paper for CYP2C19 is published

The PharmVar GeneFocus: CYP2C19 paper, the second of the GeneFocus series, has just been published by Clinical Pharmacology & Therapeutics.

PharmVar thanks all CYP2C19 experts as well as the PharmGKB team who have served on this panel and diligently curated this gene and reviewed submissions ever since PharmVar was launched back in 2017. This review provides a general overview of CYP2C19 as well as a deeper dive into the nomenclature.

The GeneFocus also provides a summary of a revision of CYP2C19*1. This revision was introduced to apply PharmVar allele definition criteria consistently across all CYP2C19 haplotypes, as well as to align definitions with the current reference sequence and its recently released LRG. Highlights of the revision include:

·       All but one *1 suballele contained g.80161A>G (I331V), which posed a conflict as this SNP is also present on many other star alleles 

·       To resolve this conflict, *1.001 (previously known as *1A) was revised to *38

o   This haplotype matches the NG_008384.3 RefSeq and LRG_584; therefore, there are no SNVs in the *38 core allele definition

o   All remaining *1 subvariants now contain g.80161A>G (I331V); consequently, g.80161A>G (I331V) has been added to the *1 core allele definition

·       *1 subvariants (with g.80161A>G (I331V)) are more commonly observed than *38

o   Commonly used genotyping platforms do not test for g.80161A>G (I331V) and thus, *1 will be assigned by default

·       The I331V amino acid change does not appear to impact function; therefore, both *1 and *38 are normal function

Changes such as the update from CYP2C19*1.001 to *38 may be viewed as ‘interruptive’. However, having standardized nomenclature that is consistently applied will greatly benefit the research and clinical PGx communities moving forward. The revision can now be found on the PharmVar page for CYP2C19.

LCD announces coverage for PGx testing under Medicare

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.

PGRN Transition

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is becoming an independent scientific society on July 1, 2020. The deadline for becoming a founding member has been extended. If you are interested in joining, please visit www.pgrn.org.

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.

Dr. Stuart Scott joins Stanford

We are pleased to announce that Dr. Stuart Scott will be joining Stanford University as a Professor in the Department of Pathology effective 1 September 2020. In addition, Dr. Scott will be Laboratory Director of the Stanford Medicine Clinical Genomics Program. Dr. Scott is moving from the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai and Sema4 (previously the Mount Sinai Genetic Testing Laboratory). He is certified by the American Board of Medical Genetics and Genomics in both Clinical Molecular Genetics and Clinical Cytogenetics and Genomics. Dr. Scott’s research interests include pharmacogenomics (PGx), cytogenomics, epigenomics, and the implementation of genomic medicine. He has long standing collaborations with Stanford’s multi-institutional efforts in PGx including PharmGKB, CPIC, PharmVar and PharmCAT.

DPYD goes live on PharmVar

PharmVar has announced the introduction of DPYD to its database. DYPD is the rate limiting enzyme involved in the catabolism of fluoropyrimidines (5-fluorouracil and capecitabine) which are used in several cancer treatment regimens. Clinical laboratories provide preemptive DPYD genotyping to avoid potentially life-threatening toxicity in patients carrying DPYD risk alleles. Annotations of clinical guidelines for DPYD are available on PharmGKB here.

Prior to its introduction to PharmVar, there was no centralized resource for DPYD nomenclature. Some of the allelic variants were assigned star allele numbers when first published (DPYD*1-*13) or were referred to by a trivial name.

Although star nomenclature based on haplotypes was initially used to name DPYD variants, this system was deemed impractical for DPYD due to the size of the gene and recombination between exons. To accommodate DPYD (and other genes with similar challenges in the future), PharmVar has developed a gene page format using rsIDs as PharmVar names instead of star allele designations.

Check out the new DPYD page at https://www.pharmvar.org/gene/DPYD. PharmVar welcomes any feedback and encourages DPYD submissions to grow its inventory.

PharmGKB response to the FDA Table for Pharmacogenetic Associations

In February, the FDA posted the Table for Pharmacogenetic Associations (PGx Table), and PharmGKB and CPIC blogged about the table a few days later.  We identified substantial areas of overlap and some differences between the gene-drug pairs listed on the FDA table and those with published CPIC guidelines. It is important to note that the FDA PGx Table, CPIC, and PharmGKB may update their content at any time. These comments reflect the PGx table as of May 2020,

As of the current posting, the evidence the FDA used to construct the PGx Table is not explicitly posted, although most of the gene-drug pairs with therapeutic management recommendations on the PGx Table have labels also listed on FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling (Biomarker Table) containing some kind of prescribing information as defined by PharmGKB. The CPIC process for creating guidelines has been published and involves field experts conducting extensive reviews of the peer-reviewed literature, all of which is cited or listed as supporting evidence in the guideline publications.

Direct comparison of which gene-drug pairs have CPIC guidelines versus which are listed on the FDA PGx Table is difficult due to the completely different manners in which the pairs are selected and ranked, as well as the different content and purposes of CPIC and the FDA PGx Table. 

Here we present our compilation tables of the gene-drug pairs on FDA’s PGx table with CPIC gene-drug pairs (some of which have guidelines, some are pending, and some are not considered actionable), PharmGKB annotations of drug labels found on FDA’s Biomarker Table, PharmGKB clinical annotations, and PharmGKB annotations of clinical guidelines published by several groups, including CPIC.  These tables are updated manually and therefore may not be current with recent changes in clinical guidelines, the FDA Biomarker Table or PharmGKB clinical annotations at the time of download.

This blog post has also been submitted as a comment to the open docket at FDA.

Announcing Dr. Kelly Caudle as co-PI of CPIC

CPIC is pleased to announce that Dr. Kelly Caudle (St. Jude Children’s Research Hospital) joins Dr. Teri Klein (Stanford University) as the co-Principal Investigator of the NHGRI U24 grant (HG 010135) that provides funds for CPIC.

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!

Join the new PGRN society!

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is transitioning to an independent, nonprofit scientific society, and all interested individuals are invited to sign up to become a member of the new PGRN!  The independent scientific society will continue many of the functions of the current PGRN, and we encourage you to join today to stay involved.  Benefits of joining the new PGRN include:

•         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

Special membership rates are available for trainees, multi-year memberships, early sign ups and those from developing countries. In addition, take advantage of the opportunity to be listed on the PGRN website as a founding member if you choose that option during signup. Sign up today at https://pgrn.regfox.com/pgrn-membership-dues.

Therapeutic Resource for COVID-19

PharmGKB has assembled a COVID-19 webpage containing therapeutic drugs from clinical trials and adjuvant therapies linking to PharmGKB annotations of gene and variant associations with these drugs.  While no trials currently discuss pharmacogenomics directly, some drugs have known associated genes and pathways.  Due to the potential QT-prolonging action of some of the drugs on this list, such as hydroxychloroquine, and the risk of concomitant treatment with other QT-prolonging agents, we have included a list of drugs associated with QT prolongation.  Additionally, we provide a list of antidepressants with Clinical Pharmacogenetic Implementation Consortium (CPIC) prescribing guidelines in light of the likelihood of depression and/or anxiety associated with the impact of COVID-19.

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. 

National COVID-19 daily health survey launched by Stanford Medicine

Stanford Medicine researchers have released a daily survey to help predict surges of COVID-19 cases in the United States.

The Stanford Medicine National Daily Health Survey initially takes two minutes to complete, with subsequent daily surveys taking only seconds. It is hoped that data from the survey, in combination with local testing results, will be able to warn healthcare providers of sudden increases in COVID-19 cases in the community before those cases reach the hospital.

Speaking to Stanford Medicine, Lawrence “Rusty” Hofmann, MD, professor and chief of interventional radiology, who is leading the survey, emphasized the need for a many people as possible to participate in the survey. “To work, this survey needs people. My hope is that people see taking this survey as their civic duty and as a way to be involved in fighting COVID-19.”

“It’s crucial to continue to take the survey every day, especially during this time of uncertainty and while we shelter in place,” Hofmann told Stanford Medicine. “But even after this initial phase is over, there will be pockets of COVID-19 cases that crop up, which is why it’s important to make a habit of it and stay consistent.”

We encourage all PharmGKB users based in the US to get involved at https://med.stanford.edu/covid19/covid-counter.html and spread the word to colleagues, friends and family.

New CPIC Guideline: CYP2C9 and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

The CPIC Guideline for CYP2C9 and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB pages for a number of NSAIDs drugs, CYP2C9, and on the CPIC website.

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).

Lamotrigine pathway published in Pharmacogenetics and Genomics

The PharmGKB lamotrigine pathway has been recently published in the journal Pharmacogenetics and Genomics.

The publication, written by Taraswi Mitra-Ghosh, now at Auburn University, and Samuel Callisto of the Univeristy of Minnesota along with collaborators, including former PharmGKB Scientific Curator Julia Barbarino, reviews both the pharmacokinetics and pharmacodynamics of lamotrigine. Lamotrigine is an antiseizure drug which has also been approved for the treatment of bipolar disorder. It is extensively metabolized in the liver primarily by UGT enzymes. Although the exact pharmacodynamic effects of lamotrigine remain unclear, it is thought that it may act as an antagonist of voltage-gated sodium channels and voltage-gated calcium channels.

Adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with lamotrigine. A number of alleles at the HLA locus which have been linked to lamotrigine-related adverse events are also reviewed in this paper.

The pathway, including a clickable image, is also freely available on the PharmGKB website.

FDA releases tables on the use of pharmacogenetic testing for specific medications

CPIC and PharmGKB applaud the release of additional guidance from the FDA on the use of pharmacogenetic testing for specific medications. Numerous members of the pharmacogenetics implementation community have asked CPIC and PharmGKB for our views on the FDA release and we identify some similarities and differences below.

There are substantial areas of overlap in those gene/drug pairs that CPIC/PharmGKB and FDA consider clinically actionable. There are also a few discordances between FDA’s table and CPIC guidelines and CPIC’s classification of gene/drug pairs as level A or B (i.e. clinically actionable). For example, CPIC recommends avoiding phenytoin for phenytoin-naïve patients with HLA-B*15:02, while phenytoin is not listed yet on the FDA tables. There are also instances in which the FDA’s table states “Refer to FDA labeling for specific dosing recommendations,” but the FDA label doesn’t include specific guidance on how much to reduce dosage or provide explicit dosing recommendations (e.g. azathioprine), information which CPIC guidelines often provide.

PharmGKB clinical annotations are based on the evaluation of published literature.  CPIC guidelines are based on evidence which is referenced in detail as part of each guideline, with expert evaluation of published literature that supports (or refutes) prescribing recommendations. At this time, it is not clear what evidence has been used by FDA to construct their tables of recommendations. It would be informative to include citations to evidence supporting these FDA tables of associations for use by others in the community.

CPIC and PharmGKB are evaluating the recent tables provided by the FDA to identify the differences between these tables and the content of the PharmGKB clinical annotations, PharmGKB annotations of the labels on the FDA Biomarker table, and CPIC guidelines.  

CPIC and PharmGKB look forward to continuing to work with the FDA and the scientific community to provide evidence-based pharmacogenetic prescribing guidelines.

Centralized presentation material repository now available from CPIC’s PGx Dissemination working group

The CPIC’s PGx Dissemination working group has developed a central repository for pharmacogenomic-related presentation materials.  Now available on the PGRN website (https://www.pgrn.org/), users will find a resource link “discussion forum” at https://forum.pgrn.org/c/clinical-implementation/pgx-dissemination-materials/25. The discussion forum provides a medium to disseminate links to PGx presentation materials and handouts.

If you have a resource that you would like to share, please visit the site.

The PGRN does not have a central server for storage of materials. Therefore, the materials must be stored external to the PGRN and contributors must provide an active link to the material(s).

You do not need to be a PGRN member to view or post to the forum. However, forum registration is required for posting materials.

The PGx Dissemination working group hopes that you will be able to contribute to building the resource and feel free to utilize the contributions of your colleagues. If you have any questions please email dfkisor@manchester.edu. The group looks forward to seeing your contributions!