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).


Monday, March 23, 2020

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.

Sunday, February 23, 2020

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-na├»ve 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.

Monday, February 10, 2020

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!

Tuesday, January 21, 2020

PharmGKB and CPIC support H.R. 3235 (updated 1/27/20)


PharmGKB and CPIC have signed up as supporters of H.R. 3235, the ‘Access to Genetic Counselor Services Act’. This bill would improve access to genetic counseling for Medicare beneficiaries by recognizing genetic counselors as independent healthcare providers who can be reimbursed for their services.

Dr. Teri Klein, co-PI of PharmGKB and CPIC, said: “Genetic counselors are vital in bringing pharmacogenomics to the clinic and helping patients to understand how their genetics can affect how they respond to drugs. By supporting H.R. 3235, we hope that many more patients will be able to access these services and receive expert advice about their genetic conditions”.

More information about H.R. 3235 can be found on the Congress.gov website.

Update 1/24/20 Comment from Dr. Teri Klein, co-PI of PharmGKB and CPIC: "For further clarification, genetic counselors are vital in bringing genomic medicine to the clinic of which pharmacogenomics is an important component."

Update 1/27/20 Comment from Julie Johnson, PharmD, Dean and Distinguished Professor, University of Florida College of Pharmacy; Founding Director, UF Health Precision Medicine Program and CPIC Steering Committee member: "I fully support qualified health professionals, who are important members of the healthcare team, being recognized with provider status.  Two key groups that are seeking such status are genetic counselors and pharmacists.   Genetic counselors are important team members for delivering genetic/genomic medicine and it is appropriate that they should be considered for provider status.  However, I believe that PharmGKB and CPIC’s initial quote about the vital role of genetic counselors in pharmacogenetics is overstated.  Based on my nearly decade-long experience leading the clinical use of pharmacogenetics data in our health system, it has become clear that the pharmaco- part of pharmacogenetics is what makes it difficult.  Genetic data often tell us that a drug or dose is not right for a given patient, but a program is ineffective if it stops there.  Guidance must also be provided on the alternative drug or dose that is right for that patient, and this requires expert knowledge in pharmacology, pharmacokinetics and pharmacotherapy.  It is the rare genetic counselor that would be an expert in these things.  Rather the members of the healthcare team best equipped for being “vital in bringing pharmacogenomics to the clinic and helping patients to understand how their genetics can affect how they respond to drugs” are pharmacists and those physicians who possess solid foundational knowledge in clinical pharmacology.  This is not to diminish the important role of genetic counselors in patient care, but rather to say that the basis for them receiving provider status cannot be the role they play in clinical pharmacogenetics.  If the focus is a highly effective healthcare team, then the members of the team must be included based on their expertise.  In the case of clinical pharmacogenetics, those experts are most likely to be pharmacists and some physicians."


Friday, January 17, 2020

PharmGKB papers in the February 2020 issue of Pharmacogenetics and Genomics


The February 2020 issue of Pharmacogenetics and Genomics has a PharmGKB double feature, with the publication of our sertraline pathway and our VIP summary for CACNA1S.

The sertraline pharmacokinetic pathway, written by Scientific Curator Dr. Rachel Huddart and collaborators, is featured on the cover of the journal. Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is used in the treatment of some psychiatric disorders, such as major depressive disorder. Metabolism of sertraline in the liver by CYP2C19 forms the basis of clinical guidelines from CPIC and the DPWG.

CACNA1S is a subunit of the dihydropyridine receptor and is expressed in skeletal muscle, where it plays a role in muscle contraction. Variants in CACNA1S have been linked to a number of myopathies as well as malignant hyperthermia, which can occur in some patients when exposed to inhaled anesthetics. The recent CPIC guideline forinhaled anesthetics includes recommendations based on CACNA1S variants. Our VIP summary, written by Senior Scientific Curator Dr. Katrin Sangkuhl with Dr.Robert Dirksen of the University of Rochester and former PharmGKB curator Maria Alvarellos, outlines the role of CACNA1S in both normal muscle function and in disease genetics. Key variants which have been associated with malignant hyperthermia are discussed in detail.

Both the sertraline pathway and CACNA1S VIP summary can be accessed on the PharmGKB website.