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.