Pharmacogenetics Implementation Research Articles

Estimated clinical utility of multi-gene pharmacogenetic testing in a retrospective cohort of gynecology patients.

This study aimed to estimate the clinical utility of performing multi-gene pharmacogenetic testing on patients undergoing gynecologic surgery/procedure by evaluating the prescribing rate of Clinical Pharmacogenetics Implementation Consortium (CPIC) level A medications and frequency of drug-gene interactions (DGIs). The electronic health record was queried for 76 current procedural terminology codes to identify gynecologic surgeries/procedures that occurred between 1 January 2015 to 31 December 2020 in patients with at least one of 152 international classification of disease codes. Prescription data for CPIC level A medications was extracted. Those enrolled in the Penn Medicine Biobank were assessed for DGIs. The cohort consisted of 7798 female patients and 682 were in the biobank. Up to 6 years following their surgery or procedure, 80% were ordered ≥1 CPIC level A medication. Over half (54%) of these medications were ordered within 3 days after their surgery or procedure. The most common CPIC level A medications ordered were ibuprofen (57%) and ondansetron (42%). Overall, 7% of the cohort had ≥1 known or predicted DGI with medications they were prescribed. Multi-gene pharmacogenetic testing may be beneficial to gynecologic surgery/procedure patients by assisting clinicians with prescribing postoperative analgesics and future medications.

Status of the implementation of pharmacogenetics in clinical practice in Spain: from regional to national initiatives.

Pharmacogenetics (PGx) has the potential to improve patient care, allowing to transform medical interventions by providing personalized therapeutic strategies. Scientific evidence supports the use of PGx in clinical practice and international organizations are developing clinical guidelines to facilitate the utilization of PGx testing. However, clinical implementation of PGx is limited and unequal worldwide. This review summarizes regional and national Spanish initiatives to implement PGx in the clinical practice. Diverse strategies to implement PGx in healthcare are applied across countries or even in the different regions of a specific country. Such was the case of Spain, a European country with 17 Autonomous Regions and two Autonomous Cities, each one with capacity to manage their own healthcare systems. Nevertheless, during the past years, many initiatives and strategies have been launched in Spain to develop different aspects of PGx. Importantly, the National Healthcare System has approved a PGx testing catalogue. This review highlights the crucial work and efforts of scientific societies (like the Spanish Society of Pharmacogenetics and Pharmacogenomics), of experts in PGx, of healthcare providers and of governmental parties in the implementation of PGx to personalize patient therapy, focused in Spain.

Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial

IntroductionGenetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside...

Limited visibility and uptake of the clopidogrel pharmacogenomic guidelines among cardiologists

Abstract Background Clopidogrel is an antiplatelet agent widely utilised in the treatment of acute coronary syndromes and following coronary interventions. Clopidogrel is a prodrug activated in the liver, mostly by cytochrome P450 2C19 that is encoded by a gene (CYP2C19). Variability in CYPC2C19 affects enzymatic activity and leads to variability in the activation and efficacy of clopidogrel. In 2011, the Clinical Pharmacogenetics Implementation Consortium (CPIC) produced the first set of detailed guidelines on the use of genetic testing to guide the clinical utilization of clopidogrel. Updates on these guidelines were published in 2013 and 2022. However, pre-prescription genetic testing is seldom performed. Purpose To establish whether these pharmacogenomics guidelines have visibility within the cardiovascular (CVD)community and have been incorporated into CVD guidelines. Methods (i) We examine the impact of the CPIC Clopidogrel guidelines released in 2013 and 2022 by looking at the citation patterns in CVD journals indexed in PubMed. (ii) We reviewed the guidelines released by the European Society of Cardiology and the American College of Cardiology on the management of coronary interventions and coronary artery disease over the last 15 years to establish whether CPIC guidelines are making any impact on practice. Results The CPIC 2022 guidelines were cited by 88 articles (49 journals) of which 13 citations (14.7%) appear in CVD journals. None of these citations are in the five major journals in which CVD guideline statements are most frequently published (Nature Review Cardiology, European Heart Journal, Circulation, Journal of the American College of Cardiology, and Journal of the American Medical Association - Cardiology). The 2013 guideline received 366 citations (183 PubMed journals). Of these, 47 were in cardiology journals (12.8%), but only 4 citations were in one of the same five major cardiology journals (2 in Nature Review Cardiology, 1 in Circulation and 1 in JAMA Cardiology). Of the 14 guidelines published by the ESC and ACC over the last 14 years, none cited the CPIC clopidogrel guidelines. Only 6 out of the 14 guidelines mentioned that the efficacy of clopidogrel was modulated by genetic factors but none of them included details or practical implications. Conclusion(s) Whilst sufficient time has not yet elapsed for the 2022 CPIC guidelines to have an impact on the specialist literature, the 2013 guidelines have had limited visibility within the CVD community. Undoubtedly, given the potential contribution of PGx, discussions on its uptakes are ongoing thus far, without resolution. Some considerations of clopidogrel genetics are diffusing into the specialty; however, from the citation evidence, it appears that CPIC clopidogrel guidelines of any vintage have had limited impact in terms of adoption and/or endorsement by cardiologists.

The Pharmacogenomics Global Research Network Implementation Working Group: global collaboration to advance pharmacogenetic implementation.

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.

One Step Ahead in Realizing Pharmacogenetics in Low- and Middle-Income Countries: What Should We Do?

Pharmacogenetics is a promising approach in future personalized medicine. This field holds excellent prospects for healthcare quality acceleration. It promotes the transition to the precision medicine era, whereby a health treatment is driven by a deeper understanding of individual characteristics by interpreting the underlying genomic variation. Pharmacogenetics has been developing rapidly since the human genome project. Many pharmacogenetics studies have shown the association between genetic variants and therapy outcomes. Several pharmacogenetics working groups have recommended guidelines for the clinical application of pharmacogenetics. However, the development of pharmacogenetics in low- and middle-income countries (LMICs) is still retarded behind. The problems mainly include clinical evidence, technology, policy and regulation, and human resources. Currently, available genome and drug effect data in LMICs are scarce. Pharmacogenetics development should be escalated with evidence proof through research collaboration across countries. The challenges of pharmacogenetics implementation are discussed comprehensively in this article, along with the prospect of pharmacogenetics-guided personalized medicine in developed countries. Stepwise is expected to help the researchers and stakeholders define the problem that hindered the pharmacogenetics application.

Publication bias in pharmacogenetics of statin-associated muscle symptoms, an umbrella review with a meta-epidemiological study

Background and aimsStatin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend dose adjustment for statin treatment according to known SLCO1B1 genotype to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias. MethodsWe searched published systematic reviews on the association between SLCO1B1 genotype and SAMS. To assessed publication bias, we used funnel plot visual inspection, Egger’s test, and the Bayes Factor (BFPublication-bias) from Robust Bayesian Meta-Analysis (RoBMA). We compared the odds ratios (ORUncorrected) from meta-analyses before and after correcting for publication bias using trim-and-fill (ORTrim&Fill) and RoBMA (ORRoBMA) methods. ResultsWe included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and six statin drugs. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger’s test (p=0.001) and RoBMA (BFPublication-bias=18). Correcting the estimate for publication bias resulted in loss of the association, from a significant ORUncorrected (1.31 95%CI [1.13–1.53]) to corrected ORs suggesting no difference: ORTrim&Fill (1.07 95%CI [0.89–1.30]) and ORRoBMA (1.02 95%CI [1.00–1.33]). This suggested that publication bias overestimated the association by 18% and 23%, respectively. Similar results were found for genotype rs4149056, simvastatin and atorvastatin. ConclusionsThe effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature, especially rs4149056. This could lead prescribers to incorrectly decreasing statin doses or even avoiding statin use, leading to a loss of the potential cardiovascular benefit of statins.

Genetic susceptibility and clinical features of CYP2D6 associated with systemic lupus erythematosus in a Chinese population.

This study aims to explore possible susceptibility genes and clinical features for systemic lupus erythematosus (SLE) patients in a Chinese population. Expanding on the results of a prior single-center observational study involving 60 systemic lupus erythematosus patients, a subsequent single-center prospective observational study was conducted on SLE patients undergoing treatment at Nanfang Hospital Affiliated to Southern Medical University from 2021 to 2023. The identification process for drug-related target genes entailed an extensive search across PharmGKB (https://www.pharmgkb.org/), the Clinical Pharmacogenetics Implementation Consortium (CPIC),and PubMed literature databases, to pinpoint common drugs and target single nucleotide polymorphisms(SNPs)for SLE. Blood samples were individually collected and genotyped using MassARRAY® high-throughput nucleic acid mass spectrometry. Genotype frequency differences were assessed through Chi-square tests against both the larger East Asian population as well as kidney transplant recipients. Data collection relied on electronic medical records, encompassing demographic details(age, gender),medication regimens(hormones, NSAIDs, hydroxychloroquine, DMARDs, biologic agents, stomach medications, calcitriol, etc.),laboratory indicators(RF, Anti-CCP antibody, ESR, CRP, anti-ANA antibodies, dsDNA antibodies, anti-SM antibodies, S m. RNP antibodies, A LT, ALB, CR, UA, WBC, PLT, HGB, Ca, K, Glu, CHOL, TG, LDL-C, HDL-C) and lupus activity scores(SLEDAI-2K). Possible disease susceptibility genes were categorized, and SPSS26 software facilitated statistical analyses. The research encompassed a total of 137 SLE patients along with 50 SNPs. After conducting statistical analyses, it emerged that there existed significant disparities in CYP2D6 gene (rs1065852) distribution when compared against allele mutation rates within both East Asian populations (p < .05) and kidney transplant patients(p < .05). Wild-type gene (GG) constituted 14% of cases while mutant gene (GA + AA) constituted 86%. Allele mutation rate (A63.6%) was significantly higher among SLE patients (RR = 0.802; p = .0355). Furthermore, the variant rs1065852 genotype (GA + AA) demonstrated significant associations with lower CRP levels, higher HGB levels, and higher HDL-C levels (p < 0 0.05). The metabolic enzyme CYP2D6 may be used as susceptibility gene for predicting systemic lupus erythematosus and are correlated with CRP and other indicators.

Implementation and Evaluation Strategies for Pharmacogenetic Testing in Hospital Settings: A Scoping Review.

Pharmacogenetic testing in clinical settings has improved the safety and efficacy of drug treatment. There is a growing number of studies evaluating pharmacogenetic implementation and identifying barriers and facilitators. However, no review has focused on bridging the gap between identifying barriers and facilitators of testing and the clinical strategies adopted in response. This review was conducted to understand the implementation and evaluation strategies of pharmacogenetic testing programs. A PRISMA-compliant scoping review was conducted. The included studies discussed pharmacogenetic testing programs implemented in a hospital setting. Quantitative, qualitative, and mixed design methods were included. A total of 232 of the 7043 articles that described clinical pharmacogenetic programs were included. The most common specialties that described pharmacogenetic implementation were psychiatry (26%) and oncology (16%), although many studies described institutional programs implemented across multiple specialties (19%). Different specialties reported different clinical outcomes, but all reported similar program performance indicators, such as test uptake and the number of times the test recommendations were followed. There were benefits and drawbacks to delivering test results through research personnel, pharmacists, and electronic alerts, but active engagement of physicians was necessary for the incorporation of pharmacogenetic results into clinical decision making. Further research is required on the maintenance and sustainability of pharmacogenetic testing initiatives. These findings provide an overview of the implementation and evaluation strategies of different specialties that can be used to improve pharmacogenetic testing.

Patterns of pharmacogenetic variation in nine biogeographic groups.

Frequencies of pharmacogenetic (PGx) variants are known to differ substantially across populations but much of the available PGx literature focuses on one or a few population groups, often defined in nonstandardized ways, or on a specific gene or variant. Guidelines produced by the Clinical Pharmacogenetic Implementation Consortium (CPIC) provide consistent methods of literature extraction, curation, and reporting, including comprehensive curation of allele frequency data across nine defined "biogeographic groups" from the PGx literature. We extracted data from 23 CPIC guidelines encompassing 19 genes to compare the sizes of the populations from each group and allele frequencies of altered function alleles across groups. The European group was the largest in the curated literature for 16 of the 19 genes, while the American and Oceanian groups were the smallest. Nearly 200 alleles were detected in nonreference groups that were not reported in the largest (reference) group. The genes CYP2B6 and CYP2C9 were more likely to have higher frequencies of altered function alleles in nonreference groups compared to the reference group, while the genes CYP4F2, DPYD, SLCO1B1, and UGT1A1 were less likely to have higher frequencies in nonreference groups. PGx allele frequencies and function differ substantially across nine biogeographic groups, all but two of which are underrepresented in available PGx data. Awareness of these differences and increased efforts to characterize the breadth of global PGx variation are needed to ensure that implementation of PGx-guided drug selection does not further widen existing health disparities among populations currently underrepresented in PGx data.

Development of a Multifaceted Program for Pharmacogenetics Adoption at an Academic Medical Center: Practical Considerations and Lessons Learned.

In 2019, Indiana University launched the Precision Health Initiative to enhance the institutional adoption of precision medicine, including pharmacogenetics (PGx) implementation, at university-affiliated practice sites across Indiana. The overarching goal of this PGx implementation program was to facilitate the sustainable adoption of genotype-guided prescribing into routine clinical care. To accomplish this goal, we pursued the following specific objectives: (i) to integrate PGx testing into existing healthcare system processes; (ii) to implement drug-gene pairs with high-level evidence and educate providers and pharmacists on established clinical management recommendations; (iii) to engage key stakeholders, including patients to optimize the return of results for PGx testing; (iv) to reduce health disparities through the targeted inclusion of underrepresented populations; (v) and to track third-party reimbursement. This tutorial details our multifaceted PGx implementation program, including descriptions of our interventions, the critical challenges faced, and the major program successes. By describing our experience, we aim to assist other clinical teams in achieving sustainable PGx implementation in their health systems.

PharmVar GeneFocus: CYP4F2.

The Pharmacogene Variation Consortium (PharmVar) serves as a global repository providing star (*) allele nomenclature for the polymorphic human CYP4F2 gene. CYP4F2 genetic variation impacts the metabolism of vitamin K, which is associated with warfarin dose requirements, and the metabolism of drugs, such as imatinib or fingolimod, and certain endogenous compounds including vitamin E and eicosanoids. This GeneFocus provides a comprehensive overview and summary of CYP4F2 genetic variation including the characterization of 14 novel star alleles, CYP4F2*4 through *17. A description of how haplotype information cataloged by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) is also provided.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP2C19 and non-SSRI/non-TCA antidepressants.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.

Implementing pharmacogenetic testing to optimize proton-pump inhibitors use among Indian population based on CPIC-CYP2C19-PPI dosing guidelines: The need of the hour.

Proton-pump inhibitors (PPIs) are widely prescribed to decrease stomach acid and treat various acid-related Gastrointestinal tract (GIT) diseases. However, genetic variations, particularly in the CYP2C19 gene, affect PPIs metabolism and efficacy. Variants in CYP2C19 can result in different rates of PPI metabolism, influencing their effectiveness. Personalized medicine strategies, such as genotyping for CYP2C19, have the potential to enhance the effectiveness of PPI therapy and patient safety. This review aims to describe the relevance of CYP2C19 genetic profiling in the indian population, including normal function (e.g. CYP2C19*1, *11, *13, *15, *18, *28, and 38), decreased function (e.g., CYP2C19*9, *10, *16, *19, *25, and 26), loss of function (e.g., CYP2C19*2, *3, *4, *5, *6, *7, *8, *22, *24, *35, *36, and *37), and increased function (e.g., CYP2C19*17) variants. This review also examines the clinical pharmacogenomics implementation consortium (CPIC)-CYP2C19-PPI guidelines to highlight the importance of pharmacogenomics (PGx)-informed personalized PPI therapy for gastroesophageal reflux disease and peptic ulcer disease treatment. On average, each person in India possesses eight pharmacogenetic (PGx) variants that can be clinically significant, underscoring the need for preemptive testing. Implementing CYP2C19 genetic testing in India requires expanding laboratory capacity, increasing accessibility in primary care, increasing public awareness, collaboration between pharmacovigilance and PGx programs, investing in advanced sequencing technologies, data management systems, and integration with electronic health records and clinical decision support systems. Addressing challenges such as genetic diversity, socioeconomic factors, health-care access issues, and shortage of trained professionals is essential for implementation. Due to the lack of definitive country-specific policies and PGx guidelines from Indian drug regulatory agencies, guidelines from international consortia such as the Clinical Pharmacogenetics Implementation Consortium and drug labeling offer crucial foundational evidence. This evidence can be used to enhance patient outcomes and ensure the safe and effective use of PPIs in India.

Implementation of pharmacogenetics for treatment of patients with acute lymphoblastic leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the most frequent pediatric leukemia; it can be defined according to chromosomic and genomic data. Cytogenetic analyses and determination of chromosomal numbers (such as hypo- or hyperdiploidy) and/or specific chromosomal rearrangements are basic for ALL classification and treatment. Even though cure rates of childhood ALL are at ~95%, pharmacogenetic aspects are of raising importance. Material and Methods: We have analyzed the literature for ALL subtypes, corresponding therapy options, and pharmacogenetic implications. Results: Data for ALL subtypes such as B-ALL, T-ALL, Ph-like ALL, DS-ALL, ETP-ALL, BCR-ABL1-like ALL are presented here. The gene polymorphism which lead to metabolizability of 6-MP are ITPA variants (94C&gt;A) and IVS2+21A&gt;C, in conjunction with TPMT (238G&gt;C, TPMT*3B 460G&gt;A and *3C 719A&gt;G and NUDT15 (415C&gt;T). For methotrexate metabolism gene polymorphisms are found for gene MTHFR as C677T and A1298C. Conclusion: In the last decade in many hospital laboratories, pharmacogenetic aspects gain more and more importance. Application of many molecular biology methods provided progress in treatment and diagnosis of ALL patients. Combination therapy is proposed as an alternative to single drug treatments.

Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity

BackgroundVoriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. MethodsCYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. ResultsVoriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. ConclusionCYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

Estimating the prevalence of potential and actionable drug-gene interactions in Irish primary care: A cross-sectional study.

Pharmacogenetics (PGx) is increasingly recognized as a strategy for medicines optimisation and prevention of adverse drug reactions. According to guidelines produced by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG), most medicines with drug-gene interactions (DGIs) are prescribed in primary care. This study aimed to estimate the prevalence of potential and actionable DGIs involving all medicines dispensed in Irish primary care. Dispensings of 46 drugs to General Medical Services (GMS) patients in the Health Service Executive Primary Care Reimbursement Service Irish pharmacy claims database from 01 January 2021 to 31 December 2021 were analysed to estimate the national prevalence of total dispensings and incidence of first-time dispensings of drugs with potential DGIs according to the CPIC and/or DPWG guidelines. Phenotype frequency data from the UK Biobank and the CPIC were used to estimate the incidence of actionable DGIs. One in five dispensings (12 443 637 of 62 754 498, 19.8%) were medicines with potential DGIs, 1878 255 of these dispensed for the first time. On application of phenotype frequencies and linked guideline based therapeutic recommendations, 2349 055 potential DGIs (18.9%) required action, such as monitoring and guarding against maximum dose, drug or dose change. One in five (369 700, 19.7%) first-time dispensings required action, with 139 169 (7.4%) requiring a change in prescribing. Antidepressants, weak opioids and statins were most commonly identified as having actionable DGIs. This study estimated a high prevalence of DGIs in primary care in Ireland, identifying the need and opportunity to optimize drug therapy through PGx testing.

Retrospective analysis: Does 5-FU dose adjustment per DPYD mutation status affect toxicity?

11172 Background: 5-Fluorouracil (5-FU) forms a cornerstone in neoadjuvant chemotherapy (NACT) regimens for solid tumors including head and neck cancers. The DPYD gene encodes for enzyme dihydropyrimidine dehydrogenase (DPD) which catalyses an essential, rate-limiting step in the metabolism of 5-FU. Heterozygous genomic alteration of DPYD (30-35% of population) result in reduced potency of DPD enzyme, while homozygous DPYD alteration (0.1-0.2% of population) results in no functional DPD. Reduced functioning of DPD leads to slower metabolism of 5-FU causing toxicity such as bone marrow suppression, cytopenias etc. The Clinical Pharmacogenetics Implementation Consortium (CPIC) have released guidelines recommending reducing the dose of 5-FU in patients with these genomic alterations of DPYD from 25% to avoiding its use based on a calculated activity score (DPYD-AS). Methods: A phase III randomized study compared a DC vs DCF regimen as NACT in technically unresectable oral cancer was published in March 2024. We utilised data from the ‘DCF’ arm of this study. Patients underwent DPYD testing and we stratified these patients based on DPYD status. In the study, patients underwent the appropriate dose reductions per the CPIC guidelines based on DPYD-AS scores. We evaluate the frequency and degree of adverse events in these groups to determine whether this dose reduction effectively reduces toxicity from 5-FU in these patients. Adverse events were graded per CTCAE. Analysis by Fishers exact test. Results: 247 patients in the DCF arm were included. 85 (34.4%) did not undergo DPYD testing. 118 (47.8%) did not have any DPYD mutation, 44 (17.8%) had heterozygous mutation while 0 had homozygous mutation. The adverse events by DPYD genotypic subgroup are shown in the table. Conclusions: There was no statistically significant difference in adverse events between the group with no DPYD mutation who received the full dose of 5-FU and the heterozygous DPYD mutation group receiving a lower 5-FU dose based on DPYD-AS score. Thus, the dose reduction as set out by the CPIC appears to appropriate. [Table: see text]

Pharmacogénétique de l’ototoxicité des aminosides : état des connaissances et des pratiques – recommandations du Réseau francophone de pharmacogénétique (RNPGx)

The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment.

Impact of CYP2D6 polymorphisms on adverse events in patients with breast cancer treated with tamoxifen: Insights from an early dose escalation trial in CYP2D6 poor metabolizers.

547 Background: Tamoxifen is widely used in treating hormone receptor-positive breast cancer. It is primarily metabolized by the CYP2D6 enzyme to yield active metabolites. However, CYP2D6 polymorphisms have been associated with a differential response to tamoxifen. In a clinical trial involving an early dose escalation of tamoxifen in poor metabolizers, we found endoxifen concentration levels similar to those of patients with extensive phenotype, and no long-term survival differences among CYP2D6 phenotypes. However, the impact of that dose escalation on side effect incidence was not addressed. Methods: In this study, we analyzed the incidence of specific side effects - osteoarticular pain, hot flashes, asthenia, and uterine alterations - in 86 breast cancer patients, differentiated by their CYP2D6 phenotype estimated according to the Clinical Pharmacogenetics Implementation Consortium. In poor metabolizers, the tamoxifen standard dose of 20 mg/day was escalated to 40 mg/day and 60 mg/day for 4 months each, and then treated with 20 mg/day until completing the treatment. Kaplan-Meier analysis and Cox proportional hazards regression model were employed to assess the relationship between the CYP2D6 phenotype and the incidence of these side effects. Results: The median follow-up time was 139.5 months. The analyses revealed that only uterine changes showed significant differences between CYP2D6 phenotypes, with a lower incidence in extensive metabolizers (P-value &lt; 0.001 in Kaplan-Meier; HR in Cox of 0.195, 95% CI 0.073 - 0.521, P = 0.001). This finding persisted after adjustment for the covariates tumor grade, size, nodal status, chemotherapy, and radiotherapy in multivariate Cox regression (HR 0.098, 95% CI 0.020 - 0.466, P = 0.004). Selection of a subgroup through Propensity Score Matching (21 vs 21) corroborated these results. The spectrum of uterine changes and pathologies included endometrial hyperplasia, polyps, adenocarcinoma, myometrial or endometrial thickening, and the presence of multiple myomas. Conclusions: Our study indicates that an early increase in tamoxifen dose in poor metabolizer patients according to CYP2D6 polymorphisms may significantly affect the incidence of uterine changes, but not the incidence of osteoarticular pain, hot flashes, or asthenia. Clinical trial information: 2007-002942-40/ES .