PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19

The PharmGKB tutorial for pharmacogenomics of drugs potentially used in the context of COVID-19 is now published in Clinical Pharmacology and Therapeutics.

The article is the first in a series of Pharmacogenomics Knowledgebase (PharmGKB) tutorials intended as a resource to help users become quickly acquainted with the wealth of information stored in PharmGKB. 

Each article will center around a specific topic, like in this publication the PharmGKB COVID-19 portal (previously blogged about it here). 

Using examples of drugs found in the portal the authors demonstrate some of the main features of PharmGKB including guideline, drug label, clinical, and variant annotations.

PharmCAT grant awarded

The co-PIs of the Pharmacogenomics Clinical Annotation Tool (PharmCAT). Dr. Marylyn Ritchie of the University of Pennsylvania and Dr. Teri Klein of Stanford University were awarded a three year grant from the National Institutes of Health National Human Genome Research Institute (NIH NHGRI) to continue and expand the project.  PharmCAT was originally created in 2016 and is a tool that: (1) extracts variants found in CPIC guideline genes from a sequencing or genotyping Variant Call Format (VCF) file, (2) assigns star alleles, diplotypes and drug phenotypes based on slightly modified PharmVar core alleles in CPIC/PharmGKB definition tables and CPIC allele function and phenotype tables, and (3) provides an HTML/PDF report including CPIC genotype-based drug prescribing recommendations.

We published the initial assessment of PharmCAT in Clinical Pharmacology and Therapeutics in 2019 (PMID: 31306493) and the beta version is currently available for testing.  Due to limited resources, PharmCAT has only been tested on a small sample of genotype data and with information from CPIC guidelines as of 2018.  The new funding will enable PharmCAT to (1) update to current CPIC guidelines and release version 1.0, (2) create a module for VCF pre-processing and quality control, (3) export an electronic health record (EHR) compatible report using Fast Healthcare Interoperability Resources (FHIR) specifications, and (4) provide the ability to run multiple VCF files at one time (batch processing).  We will announce the PharmCAT v.1.0 release on the PharmGKB blog.  Check the PharmCAT website to see updates as they happen.

This work is supported by the NIH NHGRI U24HG010862.

PharmCAT workflow below. Yellow boxes are input files for PharmCAT. Blue boxes are PharmCAT modules.  Green boxes are PharmCAT module output and input into the next module. Grey boxes are alternate input into PharmCAT.

CPIC Guideline update: HLA-B/CYP2C9 and Phenytoin/Fosphenytoin

The 2020 CPIC Guideline update for HLA-B, CYP2C19 and phenytoin dosing is now published in Clinical Pharmacology and Therapeutics. The accepted article can be accessed on the PharmGKB page for phenytoin and on the CPIC website. 

Phenytoin is an antiepileptic drug with inter-individual pharmacokinetic variability, partly due to CYP2C9 genetic variation, and  a narrow therapeutic index. The presence of the HLA-B*15:02 variant allele is associated with an increased risk of phenytoin-induced cutaneous adverse reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis. 

Literature published after the 2014 guideline was reviewed and the recommendations and supplemental information were updated. This includes updates to CYP2C9 allele assignments using the activity score (AS) system. The CYP2C9*2/*2 diplotype (AS=1) is now translated into the IM phenotype group (originally translated to PM). This is based on similar effects of CYP2C9*1/*3 (AS=1) and CYP2C9*2/*2 on metabolic ratio and dose requirements for multiple substrates. CYP2C9*3 is classified as ‘no function’ allele with an activity value of 0 for AS calculation.

For therapeutic recommendations and further details including an algorithm for suggested clinical actions based on HLA-B*15:02 and CYP2C9 genotype, please refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update.