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:
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.
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.
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
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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.
PharmVar continues to evolve and strive to offer high-quality content to our global users. To allow us to bring new clinically relevant content to PharmVar we needed to make some difficult decisions and ‘retire’ several CYP genes. This decision is based on a newly developed points-based rating system (0-100 points) that allows us to prioritize which genes to maintain and which genes to evaluate for future introduction into PharmVar. More detailed information regarding PharmVar gene content and prioritization will be posted under the GENES tab once these changes have taken effect May 12, 2023.
The following genes were not considered pharmacogenes by PharmVar due to their contribution to lipid and steroid metabolism and/or associations with disease and will be retired: CYP4A11, CYP4A22, CYP4B1, CYP17A1, CYP19A1, CYP21A2, CYP26A1, TBXAS1 and PTGIS (0 points each), though several of these genes have variant and low level clinical annotations on PharmGKB. Other databases such as ClinGen and/or ClinVar may also be consulted for variation annotations. These genes were listed by PharmVar as ‘legacy’ genes. POR (3 points) was also listed as a legacy gene. The following genes were transitioned into the PharmVar database, but never curated by an expert panel nor any additional data added: CYPs 1A1, 1B1, 2E1, 2F4, 2J2, 2R1, 2S1, 2W1, 3A7 and 3A43. These genes were not deemed to be clinically important pharmacogenes by the PharmVar Steering Committee based on having 0 points in the ranking system and will also be retired. Furthermore, the link to the archived Human Cytochrome P450 (CYP) Allele Nomenclature database record (last version by cypalleles.ki.se in 2017) will be deactivated to discourage use of outdated information (a copy can be requested through support@pharmvar.org).
If new data emerges and rankings change, a gene may be reintroduced to PharmVar.
NAT2 is currently undergoing curation and is anticipated to be transferred from the Databases of Arylamine N-acetyltransferases (NATs) to PharmVar in summer 2023. The introduction of NAT2 into the PharmVar database is timely as CPIC is initiating a guideline for the NAT2/hydralazine gene-drug pair. Additionally, NAT2 has multiple clinical annotations and mulitple annotated FDA and other regulatory agency labels.
As always, PharmVar values your feedback and suggestions support@pharmvar.org.
A new paper in Journal of Clinical Pharmacology from a group at Indiana University [PMID:37042314] implemented genotyping for CYP3A5 in a kidney transplant center.
The team used CPIC guidelines for tacrolimus dosing based on CYP3A5 genotype.
Implementation included provider education and clinical decision support in the electronic medical record.
This study reinforces that CYP3A5 genotype is an important predictor of therapeutic tacrolimus trough concentrations. They demonstrate that CYP3A5 normal and intermediate metabolizers had fewer tacrolimus trough concentrations within the desired range post-transplantation and took longer to achieve therapeutic dose than poor metabolizers. While the authors note they were underpowered to measure outcomes, there was a trend towards transplant rejection or all-cause mortality within the first year of transplant based on CYP3A5 metabolizer phenotype.
The paper highlights how, despite the guidelines from CPIC being published in 2015, the FDA label still currently only has language around race-based dose adjustment rather than giving precise guidance based on genotype:
“The FDA drug label recommends higher starting doses in individuals of African ancestry, but only 70% of African Americans are normal/intermediate metabolizers. CYP3A5 normal/intermediate metabolizers are also found among whites and Asians (East Asian and Central/South Asian) at lower frequencies (14% and 44-55%, respectively).”
“Self-reported African American race is more closely associated with CYP3A5 expresser status than other self-reported race categories, but self-reported race is not an accurate surrogate for genotype.”
The discussion is a reminder that pharmacogenomics can play a key role in reducing bias and fulfilling personalized precision medicine.
“Equality and minimization of bias in healthcare has recently become prioritized by healthcare systems as recognition of racial bias has come to the forefront in many non-healthcare aspects of society”
“One dose standard protocols and using race as a surrogate for genotype can both potentiate racial disparities in tacrolimus dosing. Routine CYP3A5 genotyping is a more accurate predictor of drug response than race alone and deemphasizes race as a biological variable in clinical care”
