Monday, September 25, 2023

Disulfiram Pathway published in Pharmacogenetics and Genomics


Substance abuse disorders are a significant public health cost [PMID: 34453125]. Prescribers have limited choices for pharmaceutical therapies with only three FDA-approved choices for alcohol use disorder and zero for cocaine use disorder. Disulfiram is an FDA-approved treatment for alcohol use disorder which is also used for cocaine use disorder. There are some preliminary studies on the PGx of disulfiram but little replication.

PharmGKB together with Dr Aneysis De Las Mercedes Gonzalez (Stanford University School of Medicine), have published PharmGKB summary: disulfiram pathway in Pharmacogenetics and Genomics, 2023 Sep 21. doi: 10.1097/FPC.0000000000000509. Online ahead of print. PMID: 37728645. It summarizes the candidate genes involved in disulfiram PGx in pharmacokinetics and action in dopaminergic, seratonergic and noradrenergic neurons and highlights the knowledge gaps.

As always interactive versions of the diagrams with underlying linked evidence, are available on PharmGKB:

Disulfiram Pathway, Pharmacokinetics,

Disulfiram Pathway, Pharmacodynamics (Cocaine and Ethanol PK)

Disulfiram Pathway, Pharmacodynamics (Dopaminergic neuron)

Disulfiram Pathway, Pharmacodynamics (Serotonergic neuron)

Sympathetic Nerve Pathway (Neuroeffector Junction)

Friday, August 18, 2023

Please Take This Survey If Your Site Conducts DPYD Genetic Testing Prior to Fluoropyrimidine Chemotherapy

Dan Hertz (DLHertz@med.umich.edu) and the DPYD Implementation Team are collecting information from sites and clinicians in the USA that conduct DPYD genetic testing prior to fluoropyrimidine chemotherapy treatment. If this applies to you, please complete this brief (<5 minutes) survey on behalf of your site before mid-September. This information will be used to develop best practice guidelines for pre-treatment DPYD testing. 

https://umich.qualtrics.com/jfe/form/SV_9Fjv2HdyQ6K6MU6

 

Thanks for your participation!


Thursday, July 13, 2023

New AMP testing recommendations for alleles in CYP3A4 and CYP3A5













The Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase have jointly published recommendations on what constitutes the minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) for CYP3A4 and CYP3A5 [PMID
:337419245].








Tier 2 CYP3A4*20


PharmGKB maintains the lists for these alleles and the tier 1 and tier 2 alleles previously published for CYP2C19, CYP2C9, VKORC1, TPMT. NUDT15 at https://www.pharmgkb.org/ampAllelesToTest


When on an allele page there is a tag to show if this allele is part of the recommended test set:


When on a gene page there is a tag to show the gene has an AMP set of test alleles plus there is a link to the AMP page from the VIP summary. 








Wednesday, July 12, 2023

Insights on CYP2C19 and phenoconversion



Phenoconversion in the PGx context is a drug-drug interaction that impacts a drug metabolizing phenotype such that it mimics the effects of a metabolizer genotype (see blog from October 2022). Historically much of the discussion on phenoconversion has focused on CYP2D6.

A new paper in Frontiers in Pharmacology investigates the phenoconversion effects of different CYP2C19 inhibitors [PMID:37361233]. 

Forty donor liver samples were genotyped for CYP2C19 *2, *3 and *17 and the metabolizer phenotypes predicted. Microsomes were assayed with the probe drug s-mephenytoin and then in the presence of strong CYP2C19 inhibitor fluvoxamine, moderate inhibitors omeprazole and voriconazole and weak inhibitor pantoprazole to look at changes in metabolizer status. 






Excerpts from paper:

“Our results demonstrate that the outcome of a DDI is dictated by both inhibitor strength and CYP2C19 activity, which is in turn dependent on genotype and non-genetic factors including comorbidities. … 

Fluvoxamine, a strong inhibitor of CYP2C19, caused 86% of *1/*17 donors to become phenotypically IM, whereas most of genetically-predicted IMs were converted to a PM phenotype (57%). In accordance with unaltered CYP2C19 activity in patients with gastroesophageal reflux disease taking pantoprazole, weak inhibition by pantoprazole did not induce phenoconversion…

However, the outcomes of DDIs with moderate inhibitors (omeprazole/voriconazole) matched less well to the proposed phenoconversion model by Mostafa et al, which predicted that NMs/IMs convert to a PM phenotype upon moderate inhibition of CYP2C19. In our study, voriconazole, which acts as a moderate CYP2C19 inhibitor, significantly reduced the drug metabolizing capabilities of CYP2C19 by approximately one level (i.e., from a phenotypic NM to a IM). As a result, 40% of the donors (12/30) were converted into IM or PM phenotypes by voriconazole. Though, none of the NMs were converted into PMs, except for one donor who already exhibited impaired CYP2C19 activity in the absence of voriconazole treatment (basal phenoconversion). For omeprazole, phenoconversion into IM or PM phenotypes was even less frequently seen, in only 10% of the donors …

Altogether, our data suggest that CYP2C19 inhibition by moderate inhibitors can result in phenoconversion, but it seems unlikely to result into a PM phenotype for wild-type *1/*1 genotypes.”


There are a number of interesting results and discussion points:


  • There is phenoconversion from disease phenotype - namely diabetes. 
  • The initial concordance for genotype to phenotype with s-mephenytoin was only 40% and the two CYP2C19*17/*17 did not have ultra-rapid UM phenotype (with Vmax in the low normal NM range). The discussion mentions “other (rare) genetic variants within CYP2C19 could also have influenced the mismatch between predicted and observed activities in our study” but it would have been useful to have ruled out *4. The *17/*17 did produce functional mRNA but the *4 is in the start codon and its impact is on translation not transcription [PMID: 9435198]. 
  • There were two *1/*1 outliers with very high UM phenotype that would be interesting to see further genetic analysis of especially given the escitalopram UM CYP2C-haplotype defined by rs2860840T and rs11188059G in [PMID: 33759177]. 


Overall, this paper shows that while phenoconversion exists for CYP2C19 based on disease status and DDIs, the impact is not a simple downgrading of phenotype (e.g. from IM to PM) that can be applied in a consistent manner across subjects. The authors show that even for strong inhibitors, phenoconversion happens in 40%-86% of subjects with no clear way to predict which subjects would experience phenoconversion and which wouldn’t. More research on how DDIs alter patient-predicted genotype to phenotype  is needed to enable better prediction of patient phenotype for PGx drug dosing recommendations.



Monday, June 26, 2023

ClinGen Pharmacogenomics Working Group (PGxWG) Survey To Close Soon

 

The ClinGen Pharmacogenomics Working Group (PGxWG)'s anonymous survey will close soon after this Friday, June 30, 2023. Our goal is to gather opinions and feedback regarding the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. If you have not yet had the chance to fill it out or pass it along, please do so soon! 

Pharmacogenomics expertise is not required - we are also looking for responses across the broader global genetics and medical communities as well (clinicians, pharmacists, labs, genetic counselors, etc.) All responses are appreciated, no matter who you are or where you are in the world. If you’ve previously completed the survey, we appreciate your contribution and there's no need to submit a second response. 

The survey can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4.  We sincerely appreciate your time and participation, and your willingness to help.

Friday, June 9, 2023

ClinPGx Sessions at PGRN 2023 Conference and ClinGen Summer Workshops

At the upcoming PGRN 2023 annual conference in Memphis, Dr. Teri E. Klein, the principle investigator for PharmGKB, ClinGen, CPIC and PharmCAT,  will hold a town hall discussion on ClinPGx: a single integrated resource for Pharmacogenomics (PGx). Dr. Klein will discuss the challenge of the separation of pharmacogenomic resources from clinical genomic resources, and present a long-term, conceptual framework for broadly integrating the available PGx resources into a single resource, ClinPGx. 

Dr. Klein will also present at the upcoming ClinGen 2023 Summer Workshop Series on June 16 11am PT. Please come join us. We are actively seeking feedback from the PGx and genomics community on the interest and development of ClinPGx to facilitate the incorporation of PGx into standard of care. Zoom link below: 

June 16th, 2023, 11am PT/ 2pm ET 

Join Zoom Meeting : 

https://acmg.zoom.us/j/87027015818?pwd=S2U2OTFhQ1oranFZZjNlTEhHN0FlUT09 

Meeting ID: 870 2701 5818 

Passcode: 83854960 

One tap mobile 

+16699006833,,87027015818# US (San Jose) 

+17193594580,,87027015818# US 


ClinGen Pharmacogenomics Working Group (PGxWG) Survey Open Until June 30, 2023

The ClinGen Pharmacogenomics Working Group (PGxWG)'s anonymous survey is OPEN until June 30, 2023. Our goal is to gather opinions and feedback regarding the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. Please help disseminate to ALL (clinicians, pharmacists, labs, genetic counselors, etc.). We are looking for BROAD global participations - please send to your friends and colleagues too!  If you’ve previously completed the survey, we appreciate your contribution and there's no need to submit a second response. 

The survey can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4.  We sincerely appreciate your time and participation, and your willingness to help.