Tuesday, May 26, 2020

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.

Monday, May 18, 2020

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.

Friday, May 1, 2020

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!

Wednesday, April 29, 2020

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.

Friday, April 17, 2020

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. 

Monday, April 13, 2020

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.

Wednesday, March 25, 2020

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).