Friday, February 19, 2021

PharmGKB and CPIC curated information displayed on ClinGen

PharmGKB and CPIC partnered with ClinGen last summer to bring curated pharmacogenomics (PGx) to the resource which defines the clinical relevance of genes and variants in the human genome. A new Pharmacogenomics column has been added to ClinGen's curated gene categories.  130 PGx genes curated by PharmGKB and/or CPIC are now listed on the ClinGen website with links back to the PharmGKB and CPIC websites for more detailed information.

ClinGen displays all gene-drug pairs from PharmGKB with Level 1 & 2 Clinical Annotations along with (1) a link to the relevant PharmGKB drug page, (2) the highest annotation level for the gene-drug pair (linked to the explanation of PharmGKB's Levels of Evidence), (3) the date of the last update and (4) a link to view all PharmGKB Clinical Annotations for that gene-drug pair.

ClinGen also displays all CPIC gene-drug pairs with levels A-D.  Where applicable, these are grouped by CPIC guideline with (1) a link to the CPIC guideline page and (2) gene-drug pairs list page.  Gene-drug pairs with provisional CPIC levels (i.e. those awaiting further evaluation and potentially guideline development) link to the gene-drug pairs list page. 

Thursday, February 18, 2021

Plavix manufacturers to pay $834 million to state of Hawaii

Bristol-Myers Squibb Co and Sanofi, the manufacturers of Plavix (clopidogrel) have been ordered to pay over $834 million to the state of Hawaii after failing to warn about the drug’s potential health risks to patients with combinations of CYP2C19 variants which result in a CYP2C19 poor metabolizer status.

Clopidogrel is metabolized to its active metabolite by CYP2C19, as shown in the PharmGKB clopidogrel pathway. Patients carrying CYP2C19 no function alleles (e.g. CYP2C19*2) have reduced or no conversion of clopidogrel to the active metabolite, which puts them at an increased risk of cardiovascular events. The CPIC guideline for clopidogrel recommends that CYP2C19 intermediate and poor metabolizers receive alternative antiplatelet therapy.

The companies were found to have violated Hawaii’s consumer protection laws by not disclosing that Plavix would be ineffective for as many as 30% of patients in Hawaii, many of whom are of Asian and Pacific Islander descent. Some CYP2C19 no function variants, such as CYP2C19*2, are found at higher frequencies in Asian and Pacific Islander populations compared to their frequency in European populations (see the CYP2C19 allele frequency table).

Judge Dean Ochiai ruled that Bristol-Myers Squibb Co and Sanofi “knowingly placed Plavix patients at grave risk of serious injury or death in order to substantially increase their profits” over a 12-year period from 1998 to 2010. Information about the effect of CYP2C19 no function alleles on the efficacy of Plavix was added to the drug label in 2009, and a Black Box warning to consider alternate therapy for CYP2C19 poor metabolizers was added in 2010. PharmGKB has annotated the Plavix label and highlights pharmacogenomic information found within the label.

Hawaii Attorney General Clare Connors emphasized the growing impact of pharmacogenomics on the pharmaceutical industry: “The order entered by the court today puts the pharmaceutical industry on notice that it will be held accountable for conduct that deceives the public and places profit above safety”.

In a joint statement, the companies said that “the overwhelming body of scientific evidence demonstrates that Plavix is a safe and effective therapy, including for people of Asian descent.” and that they plan to appeal.

Tuesday, February 16, 2021

HGVS annotations now available on PharmVar

We are excited to share that PharmVar is now providing HGVS annotations in addition to their more traditional annotations. To accommodate different styles, the Variation Window has been redesigned.

Clicking on any SNV on a PharmVar gene page will activate the variation window. The example shown below is for the CYP2C9*2 variant c.430C>T. This view provides SNV positions across all sequences, the link to the NCBI dbSNP identifier (rs number) as well as SNV frequency. There is also a bar providing the option to display all haplotypes with the selected variant.

The top portion of the variation window displays SNV coordinates according to Human Gene Variation Society (HGVS) nomenclature on the gene, transcript and genome (GRCh37 and GRCh38) levels. Coordinates are displayed as obtained through the NCBI Variation Services. 

The middle portion of the variation window displays SNV positions ‘PharmVar-style’ on the gene, transcript and genome (GRCh37 and GRCh38) levels giving positions for both count modes and detailing the reference and variant nucleotides. 

It is noted that HGVS and ‘PharmVar-style’ positions may differ for insertion/deletion variants in some instances, which is most likely explained by how sequences are aligned. Also, PharmVar displays single nucleotide insertions as ‘ins’ while HGVS displays them as duplications or ‘dup’. Additional details and examples are can be found in the PharmVar ‘Standards’ document. HGVS annotations are also accessible via API services.

PharmVar welcomes any feedback you may have through 

Wednesday, February 10, 2021

Update to FDA-approved drug label annotations

In February 2020, we blogged about the FDA's newly released Table of Pharmacogenetic Associations. Since then, there has been much interest in understanding how that table was created, how it compares to the information on the drug labels, and how it compares to the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling, which has existed for many years and is routinely curated by PharmGKB.  With this in mind, PharmGKB has created a section on its FDA-approved drug label annotations for information from the Table of Pharmacogenetic Associations (Figure 1). 

Figure 1. Screenshot of part of the FDA-approved drug label annotation for codeine.

We also have a new landing page specifically for FDA-approved drug label annotations that can be sorted and filtered by different criteria in the column headings, including the category of the drug from the Table of Pharmacogenetic Associations ("FDA PGx Association"). The table can be downloaded in TSV format as either the full or filtered version (Figure 2).

Figure 2. Screenshot of the FDA Drug Label Annotations table.

This table can be found on the PharmGKB homepage under the "Annotation" and "Clinical" section (Figure 3) and is in addition to our Drug Label Annotations table that includes labels from multiple regulatory agencies found at the top left corner of the homepage.

Figure 3. PharmGKB homepage.

As a reminder, PharmGKB drug label annotations provide (1) a brief summary of the PGx in the label, (2) an excerpt from the label, including any guidance from the label for patients with a particular genotype/metabolizer phenotype if it exists, (3) specific variants discussed on the label, particularly if there is prescribing guidance for them, and (4) a downloadable highlighted label PDF file.  PharmGKB also "tags" labels to indicate certain information, including: 

    (5) the "PGx Level" tag ("Testing required", "Testing recommended", "Actionable PGx" and "Informative PGx") which is the PharmGKB interpretation of the level of action implied in each label

    (6) the "Dosing Info" tag which indicates dosing information based on genotype/metabolizer phenotype exists on the label

    (7) the "Alternate Drug" tag which indicates if a drug is either indicated or contraindicated based on genotype/metabolizer status on the label

    (8) the "Prescribing Info" tag which indicates if any guidance from the label for patients with a particular genotype/metabolizer phenotype exists on the label

    (9) the "Cancer Genome" tag which indicates if the label discusses a gene or variant present in a tumor/cancer cell

    (10) the "On FDA Biomarker List" tag if the label is on the FDA's Table of Pharmacogenomic Biomarkers in Drug Labels.

Figure 4. Screenshot of the FDA-approved drug label annotation for irinotecan to illustrate the types of information found in a label annotation.

Wednesday, January 20, 2021

CYP2B6 GeneFocus paper published

The latest paper in the PharmVar GeneFocus series, looking at CYP2B6, has now been published in Clinical Pharmacology and Therapeutics.

CYP2B6 is the only member of the CYP2B subfamily to encode a functional enzyme. Variation in this gene impacts the metabolism of several clinically important drugs, including efavirenz (see the CPIC guideline and annotation on PharmGKB), methadone and bupropion. 

The paper gives an overview of CYP2B6 genetic variation and outlines the gene’s previous nomenclature system prior to being catalogued by PharmVar. Details of CYP2B6 resources on PharmGKB and CPIC as well as reference materials for genetic testing are also provided.

CYP2B6 has now been curated into PharmVar, with some alleles revised to remove SNPs with little or no evidence available to show that they caused a change in CYP2B6 function. Users should also note that the *16 and *18 alleles have been consolidated, with *16 now listed as a suballele of *18. All changes have been recorded and can be found on the PharmVar page for CYP2B6.  PharmGKB and CPIC will be updating CYP2B6 information accordingly.

PharmVar would like to thank all members of the CYP2B6 gene expert panel for their efforts in curating this important gene.

Thursday, January 14, 2021

CPIC opioids guideline now annotated on PharmGKB

The CPIC guideline for opioid therapy and CYP2D6, OPRM1 and COMT was recently published in Clinical Pharmacology and Therapeutics and has now been annotated on PharmGKB. This guideline is an update to the CPIC guideline for codeine and CYP2D6, but now includes information on two other genes, OPRM1 and COMT, and a number of other opioids.

The guideline gives specific dosing recommendations for CYP2D6 and three drugs; codeine, tramadol and hydrocodone. Codeine and tramadol are not recommended for CYP2D6 ultrarapid metabolizers due to an increased risk of toxicity, nor for CYP2D6 poor metabolizers, where there is a risk of insufficient analgesia. The authors also recommend that CYP2D6 intermediate and poor metabolizers be monitored for analgesic response following the initiation of hydrocodone therapy. If patients with either of these metabolizer phenotypes fail to have an analgesic response to hydrocodone, a non-codeine or non-tramadol opioid can be considered.

Studies looking at the effects of variants in OPRM1 and COMT on opioid response were also assessed as part of this guideline update. OPRM1 encodes the mu opioid receptor, which binds to many opioids, while COMT codes for the enzyme Catechol-O-methyltransferase. COMT methlyates catecholamines and is thought to regulate pain perception. Due to the low quantity and/or quality of available evidence, the authors specifically issued no recommendations for opioid dosing based on OPRM1 or COMT variants. This is an important feature of the guideline, as testing for variants in these two genes in relation to opioid response is included in some pharmacogenomic tests.

In order to fully capture the size and complexity of this guideline, it is covered by multiple guideline annotations on PharmGKB, including extended dosing guidelines with genotype pickers for codeine, tramadol and hydrocodone. All guideline annotations can be accessed via the PharmGKB Clinical Guideline Annotations page. The full guideline manuscript, supplement and relevant implementation resources are also freely available on the CPIC website.

Thursday, January 7, 2021

New PharmGKB pathway for Cannabidiol Pharmacokinetics

PharmGKB released a new pharmacokinetics pathway for Cannabidiol, a phytocannabionoid found in the Cannabis sativa plant approved to treat two rare forms of epilepsy. 

The pathway was produced by graduate student Kris Oreschak from the University of Colorado Denver Anschutz Medical Campus with guidance from scientific curator Dr Caroline F. Thorn. While there are currently no published studies documenting the pharmacogenomics of cannabidiol, many pharmacogenes are involved in its metabolism presenting future opportunities to look at variable responses. 

View all pathways at PharmGKB