Thursday, February 29, 2024

ClinPGx 2024 Registration and Abstract Submission Open

 

REGISTRATION OPEN

In collaboration with CPIC, PharmGKB, PharmCAT and PharmVar, the Penn Institute for Biomedical Informatics will be hosting the ClinPGx 2024: Knowledge, Implementation, Education meeting on June 20th and 21st, 2024 in Philadelphia, PA. This meeting will provide educational content to cover all aspects of PGx implementation, including knowledgebases, implementation strategy, informatics, use of AI in precision medicine, clinical laboratory insights, and more.

Participants are invited to submit abstracts for the poster sessions. You must be registered for the meeting before your abstract will be accepted.

Please note breakfast & lunch will be provided all conference days.


Registration and detailed agenda


REMINDERS / DEADLINES:

March 22, 2024: Deadline for Abstract Submission. Abstract submission form link here.

April 30, 2024: Deadline for $350 Registration Fee (Starting May 1st, registration fee will be $450)

May 20, 2024: Deadline for Hotel Reservations. Click HERE for hotels offering special rates.

June 1, 2024: Deadline to register for the event.




Thursday, January 25, 2024

Release of Additional PharmGKB Pediatric Drug Summaries

A new round of PharmGKB's pediatric drug summaries is now available on PharmGKB under the Pediatric Focus.

To view the site with the focus active, please select the "Focus" button in the upper right-hand corner and toggle the "Pediatric Focus" setting.

Users can also access the Pediatric Focus on the Focus landing page, or by typing pediatric.pharmgkb.org

These pediatric drug summaries contain key information relevant to prenatal, postnatal, and pediatric populations, manually curated from PharmGKB annotations, pathways, CPIC guidelines, and FDA-approved drug labels.

Drugs with newly available summaries include:
PharmGKB continues to add to the list of drugs with pediatric summaries. To browse all drugs with available pediatric summaries, please check out the PharmGKB Pediatric Dashboard.

 

Wednesday, December 20, 2023

Updates to Drug Label Annotation Tags and Criteria for PGx levels

PharmGKB has made some changes in the Drug Label Annotation process to clarify the pharmacogenomic (PGx) relationships of biomarkers. PharmGKB curates all drug labels on the FDA’s Table of Pharmacogenomic Biomarkers in Drug Labeling and previously attempted to classify all labels with PharmGKB-created “PGx levels” . However many of the relationships do not fit standard pharmacogenomic definitions. It is clear from over a decade of label curation that many labels, including many on the FDA Biomarker list, mention genes, variants, chromosomal rearrangements, testing, drug-drug interactions and other incidental information but do not explicitly provide pharmacogenomic clinical guidance or information. Accordingly, we have altered the PGx level definition for “Informative PGx”, and created a new PGx level “Criteria Not Met” and a new drug label annotation tag "Indication”.

PharmGKB also attempts to identify and curate drug labels from other regulatory agencies for drugs with annotated FDA labels. Labels from other regulatory agencies may or may have similar information to the FDA-approved label, but sometimes the label cannot be found after a search. Previously, if a label was not found, the entry on the Drug Label Annotations Landing page was left blank. However, if a search has not yet been done, the entry is also blank, which led to ambiguity. PharmGKB now states when a label is not found.  

The main changes we are implementing are:


1. to define where the testing requirement is part of the indication of the drug.


The Indication tag is defined as “The gene or variant is an Indication for the drug, or the drug is for use in a specific population defined by the gene or variant(s), according to the label.” There are many anti-cancer drug examples of this including adagrasib and afatiniband currently 128 out of 182 indication-tagged drug labels regard variants and genes in the cancer genome. Additional non-cancer examples are alglucosidase alfa, a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease, and desmopressin, a synthetic vasopressin analog that is FDA approved to increase plasma levels of factor VIII activity in patients with hemophilia A (F8 deficiency) and von Willebrand’s disease Type I. 


2. to update the criteria for "informative PGx" level and to indicate where the information on the label does not meet our criteria for pharmacogenomics with tag "Criteria not met". Previously, these would have been lumped into “Testing required” and “Informative PGx” tags, respectively.


The Informative PGx level is now defined as “The label contains information stating that particular gene/protein/chromosomal variants or metabolizer phenotypes do NOT affect a drug’s efficacy, dosage, metabolism or toxicity. Or, the label states that particular variants or phenotypes affect a drug’s efficacy, dosage, metabolism or toxicity, but this effect is NOT “clinically” significant”.


The Criteria not met level is defined as "the labels appear or appeared on the FDA Biomarker List but do not currently meet the requirements to be assigned as “Testing required”, “Testing recommended”, “Actionable PGx” or “Informative PGx”.  PharmGKB annotates every label that appears on the FDA Biomarker list, regardless of whether we would otherwise annotate the label. PharmGKB also checks European Medicines Agency (EMA), and Health Canada/Santé Canada (HCSC) databases for the same drug label and annotates them if they contain pharmacogenomics information and applies the PGx level tags as appropriate.”



An example that changed from "informative PGx" to "criteria not met" is blinatumomab, which is listed on the FDA table of biomarkers with BCR-ABL and CD19. The mechanism of action is via CD19 but the label does not have information on variants of CD19 and any changes in efficacy or toxicity. The label includes information on clinical studies that included patients with Philadelphia chromosome negative Refractory B-cell Precursor ALL.


Example where labels language is different across the different agencies:

Lomitapide (https://www.pharmgkb.org/chemical/PA166114922/labelAnnotation) - FDA and HCSC criteria not met, EMA testing required.

Mavacamten (https://www.pharmgkb.org/chemical/PA166272922/labelAnnotation) -  FDA and HCSC label for Mavacamten has actionable PGx whereas the EMA label requires CYP2C19 genotyping. 


3. To show when a search was performed for the label but the curator was unable to find the document at the stated repository. 


Entries in the Drug Label Annotations landing page now show “No document available” if a label could not be found. See an example screen shot from the landing page below.



4. To enable accession to the label source directly for FDA and EMA labels.


At the bottom of the drug label annotation page, there is a section titled “Source” that has a link to download the drug label that is the source of the information in the annotation. This label is typically also available in the body of the annotation. The downloadable PDF file is usually highlighted with relevant PGx and drug-drug interaction information. See an example screen shot from the label annotation for abacavir below.



When we began annotating FDA-approved drug labels over a decade ago, we did not anticipate how widespread the use of our label annotation tags would become. Many groups have published papers that discuss PGx and FDA labels using the relative numbers of our tags (e.g. PMIDs 26693845, 25317785, 25521333, 29205206, 29722046, 34412102, 28073152). In 2012 we had 113 label annotations from the FDA; we now have over a thousand label annotations across global sources. As stated in our blog from 2013, “Curators have tried to define clearly how they interpret the level of PGx information on labels, resulting in definitions that are really a rather long list of criteria. These definitions may change over time as new label wording comes up and definitions need to adjust for these new cases.” Indeed, the PGx level definitions have been tweaked over the years to accommodate the unique nuances of labels encountered during the curation process, and we continually work to apply the changes across labels from the FDA and then cross-check against other international regulatory bodies, such as the EMA and HCSC. We are pleased that the community had found our label annotations useful and strive to improve and expand the annotations for future use. We hope these updates make the drug label annotations more consistent and evidence more transparent. Please contact us at feedback@pharmgkb.org with questions.

Monday, December 18, 2023

CPIC Guideline for Potent Volatile Anesthetic Agents and Succinylcholine - RYR1 variant update

The original guideline, supplement, and the supporting gene and drug files are available on the CPIC website. Annotations of the guideline, including an interactive genotype picker tool are available on the PharmGKB website.

Subsequent to the publication of the CPIC Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes (PMID 30499100), the ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel (VCEP) developed and published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility (PMID 35849058). CPIC has added an additional 291 variants and updated the RYR1 allele definition, frequency, and functionality tables accordingly (additional details can be found in the notes tab of the RYR1 allele functionality table). 

Pathogenic and likely pathogenic variants are assigned a CPIC function of Malignant Hyperthermia associated, variants of uncertain significance (VUS) are mapped to uncertain function, and benign and likely benign variants are assigned normal function. 

Additionally, CPIC has created a RYR1 diplotype to phenotype table. RYR1 phenotypes are determined based on the function combinations of two RYR1 variants. The RYR1 diplotype to phenotype table contains all possible combinations of two RYR1 variants included in the RYR1 allele functionality file. In case >2 variants are found, the variants with Malignant Hyperthermia associated function should be used first. If 2 Malignant Hyperthermia associated variants are found, those are assumed on different chromosomes.




Monday, November 27, 2023

New Fluoropyrimidine Toxicity Variants Reported in DPYS and PPARD

A recent paper highlights new variants and genes associated with severe fluoropyrimidine-related toxicity in patients who were genotyped as negative for the four DPYD variants the European Medicines Agency recommends testing for.

Online ahead of print in the Human Genomics journal is De Mattia et al "The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity" [PMID: 37946254].

The study sequenced 120 patients with fluoropyrimidine induced grade 3-5 toxicity confirming they lacked DPYD*2A, DPYD*13, c.2846A > T, c.1236G > A-HapB3. The paper reports rare and common variants including DPYS rs143004875-T and PPARD rs2016520-T which were associated with increased risk of severe toxicity.

Thursday, November 9, 2023

Save the Date: ClinPGx 2024 Meeting

In collaboration with CPIC, PharmGKB, PharmCAT and PharmVar,  the University of Pennsylvania, Penn Center for Precision Medicine will be hosting the ClinPGx 2024: Knowledge, Implementation, Education meeting June 20th and 21st, 2024 in Philadelphia, PA. The meeting will provide educational content to cover all aspects of PGx implementation including knowledgebases, implementation strategies, informatics, use of AI in precision medicine, clinical laboratory insights, and more. Additional details to soon.

Tuesday, September 26, 2023

Frequencies of Pharmacogenomic Alleles across UK Biobank Biogeographic Groups Published

We are happy to announce the publication of our latest research article in the American Journal of Human Genetics (AJHG), titled “Frequencies of Pharmacogenomic Alleles across Biogeographic Groups in a Large-Scale Biobank.” The paper is now available online on the AJHG website.

Genetic biobanks provide rich data sets to investigate population-specific pharmacogenomic (PGx) allele frequencies and the implications of equitable and inclusive implementation. Using an integrated UK Biobank 200K genetic dataset (N = 200,044), we estimated the pharmacogenomic (PGx) allele frequencies for seventeen (17) pharmacogenes in five (5) biogeographic groups. 
  • Pharmacogenes included ABCG2, CACNA1S, CYP2B6, CYP2C19, CYP2C9, CYP3A5, CYP4F2, DPYD, G6PD, IFNL3, NUDT15, RYR1, SLCO1B1, TPMT, UGT1A1, and VKORC1. CFTR and the CYP2C cluster variant (rs12777823) were also investigated. CYP2D6 alleles that could be determined from VCF, and therefore not including structural variants, were also predicted.
  • The five (5) biogeographic groups are Europeans (n = 187,660), Central/South Asians (n = 3,460), East Asians (n = 637), African Americans/Afro-Caribbeans (n = 1,926), and Sub-Saharan Africans (n = 1,235)
  • Frequencies of PGx alleles, diplotypes, phenotypes, and/or activity scores, if applicable, were reported for each gene in each biogeographic group.

We found that 100% of the UK Biobank participants harbored at least one genetic variant found in known PGx haplotypes. 

The main takeaways messages are:

1. UK Biobank PGx frequencies complemented the CPIC frequency tables.

2. This study reported frequencies for a nontrivial number of PGx alleles that are rare or seldom tested, especially in the non-European group.

3. There are uncataloged PGx alleles.


PGx frequencies estimated from this study will be disseminated via PharmGKB. Biobank-derived allele frequencies can provide guidance for future PGx studies and clinical genetic test panel design, and better serve individuals from wider biogeographic backgrounds.