Preemptive Pharmacogenetic Testing Research Articles

Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.

A survey on awareness, knowledge and preferences toward genetic testing among the United States general public.

Aim: To understand awareness, knowledge and preferences regarding genetic testing among the USA general public. Methods: A cross-sectional online survey using a Qualtrics Panel. Results: Among 1600 respondents, 545 (34%) were White, 411 (26%) Black, 412 (26%) Hispanic or Latin(x)and 232 (15%) Asian. Most had heard of ancestry testing (87%) and genetic health risk testing (69%), but a third thought inherited genes were only a little or not at all responsible for obesity (36%) and mental health (33%). The majority preferred pre-emptive pharmacogenetic testing (n=74%) compared with reactive testing. Statistically significant differences between racial/ethnic groups and rural-urban respondents were observed. Conclusion: Most preferred pre-emptive pharmacogenetic testing; however, about one-quarter preferred reactive testing. Preferences should be discussed during patient-clinician interactions.

Feasibility of preemptive pharmacogenetic testing and improvement of medication treatment satisfaction among medically underserved patients.

Previous findings suggest that medically underserved patients are prescribed medications with pharmacogenetic (PGx) guidelines at a high frequency. Thus, underserved patients may especially benefit from PGx testing, but little evidence exists regarding the effect of testing in this population. This pilot study aimed to generate key feasibility data and explore clinical outcomes of PGx implementation in underserved populations. Black and Latino patients were recruited from an outpatient clinic and underwent PGx testing. Feasibility measures included enrollment metrics and actionable genotype frequencies. The primary clinical outcome was patient medication treatment satisfaction 6 months after testing. Implementation outcomes included the number of healthcare provider encounters and medication changes within the 6-month follow-up. Effectiveness outcomes included medication adherence, patient-perceived test value, and time spent discussing medications with providers. Ninety-nine patients completed the study. Proton-pump inhibitors were the most frequent PGx drug class prescribed at baseline (61%) followed by nonsteroidal anti-inflammatory drugs (36%). Patients with an actionable genotype constituted 96% of the population, whereas 28% had an actionable genotype related to their PGx drug. Patient treatment satisfaction significantly increased over the 6 months after PGx testing. In addition, medication adherence and the number of provider encounters significantly increased over the study period. In a pilot study, preemptive PGx testing was feasible in primary care clinics, improved patient treatment satisfaction and adherence, and increased the number of provider encounters in medically underserved patients. Future clinical trials are warranted to assess the long-term effects of PGx testing in a larger diverse patient population.

#6812 ON THE TOP PHARMACOGENETICS STUDY EXTRACTED FROM EXOME SEQUENCING DONE FOR CHRONIC KIDNEY DISEASES OF UNKNOW ORIGIN

Abstract Background and Aims A recent study from a large cohort published by the Ubiquitous Pharmacogenomic Consortium demonstrates the interest of pre-emptive pharmacogenetic panel testing, with a 30% reduction rate of clinically detectable side-effects. Our laboratory routinely performs diagnostic exome sequencing (ES) for adult patient with kidney disease and more than 2000 patients have been analyzed to date. Patient with chronic kidney diseases (CKD) could benefit from pharmacogenetics information, since they are often polymedicated and efficacy or safety of their medications are known to be influenced by the genetic background. We studied if meaningful pharmacogenetics information could be delivered from exome sequencing data provided for CKD, either retrospectively or prospectively. Method We selected 214 variants of pharmacogenetics relevance, based on evidence and frequency criteria. We evaluated their depth of coverage on 300 patients randomly selected in our CKD cohort. Results Eleven of those 214 variants were not covered by ES. Three of 11 variants were in UGT1A1 and were excluded from analysis since this information is only relevant for Irinotecan treatment. The remaining 8 variants fall in CYP2C19, CYP3A5, CYP3A4, CYP2D6, HLA B (B15:02), HLA A (A31:01), IFNL3, VKORC1 genes: we completed exome data by targeted sanger sequencing for these variants. One challenging region is CYP2D6 given high sequence homology with CYP2D7 and CYP2D8: to assess if we could reliably call variants in this region, we used 7 additional Coriell samples, as 8 others were also assessed with an orthogonal technique. We were able to properly detect variants in these complex regions in all cases, including hybrid genes. Conclusion Our preliminary data show that exome sequencing, initially ordered for CKD, could also be used to deliver pharmacogenetic meaningful information, by adding a few targeted genotyping assays. We currently evaluate the clinical utility and impact of pharmacogenetics in our CKD cohort prospectively.

Implementation of Clinical Cytochrome P450 3A Genotyping for Tacrolimus Dosing in a Large Kidney Transplant Program.

Tacrolimus is a calcineurin inhibitor with a narrow therapeutic range and is metabolized by cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5. The Clinical Pharmacogenetic Implementation Consortium published evidence-based guidelines for CYP3A5 normal/intermediate metabolizers prescribed tacrolimus, yet few transplant centers have implemented routine testing. The objective of this study was to implement preemptive CYP3A genotyping into clinical practice in a large kidney transplant program and to evaluate workflow feasibility, potential clinical benefit, and reimbursement to identify barriers and determine sustainability. Preemptive pharmacogenetic testing for CYP3A5 and CYP3A4 was implemented in all patients listed for a kidney transplant as part of standard clinical care. Genotyping was performed at the listing appointment, results were reported as discrete data in the electronic medical record, and education and clinical decision support alerts were developed to provide pharmacogenetic-recommended tacrolimus dosing. During this initial phase, all patients were administered standard tacrolimus dosing, and clinical and reimbursement outcomes were collected. Greater than 99.5% of genotyping claims were reimbursed by third-party payers. CYP3A5 normal/intermediate metabolizers had significantly fewer tacrolimus trough concentrations within the target range and a significantly longer time to their first therapeutic trough compared to poor metabolizers. The challenge of tacrolimus dosing is magnified in the African American population. The US Food and Drug Administration drug label recommends increased starting doses in African ancestry, yet only ≈66% of African Americans in our cohort were normal/intermediate metabolizers who required higher doses. Routine CYP3A5 genotyping may overcome this issue by using genotype over race as a more accurate predictor of drug response.

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study

The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. European Union Horizon 2020.

Utilization of Drugs with Pharmacogenetic Dosing Recommendations in Switzerland: A Descriptive Study Using the Helsana Database.

In Switzerland 167 drugs on the market contain information about pharmacogenetics in their drug label (PGx drug). Preemptive pharmacogenetic testing is reimbursed by health care insurance for only seven drugs (abacavir, carbamazepine, 6-mercaptopurine, azathioprine, 5-fluorouracil, capecitabine, and irinotecan) although, it is proposed to be a cost-effective approach to personalized medicine. The aim of this study was to describe the use of PGx drugs and their corresponding genes in Switzerland. We identified 90 drugs with dosing recommendations from the Pharmacogenetic Knowledgebase involving 24 genes. We assessed the utilization of those drugs between 2016 and 2020, using claims data from a large Swiss insurance company (Helsana). Of 841 491 persons with drug claims during the whole study period, 78.7% were exposed to PGx drugs. Ibuprofen, pantoprazole, and tramadol had the highest number of users. Seven genes (CYP2C19, CYP2C9, CYP2D6, SLCO1B1, HLA-B, MT-RNR1, and VKORC1) were responsible for over 95% of all potential drug-gene interactions. The prevalence of PGx drug prescriptions is high in the Swiss population. Therefore, intensified preemptive testing may be a useful option as a substantial amount of the Swiss population might benefit.

Pharmacogenetic Analysis of Voriconazole Treatment in Children.

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections.

Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation

BackgroundPharmacogenetic (PGx) testing for germline variants in the DPYD and UGT1A1 genes can be used to guide fluoropyrimidine and irinotecan dosing, respectively. Despite the known association between PGx variants and chemotherapy toxicity, preemptive testing prior to chemotherapy initiation is rarely performed in routine practice.MethodsWe conducted a qualitative study of oncology clinicians to identify barriers to using preemptive PGx testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. Each participant completed a semi-structured interview informed by the Consolidated Framework for Implementation Research (CFIR). Interviews were analyzed using an inductive content analysis approach.ResultsParticipants included sixteen medical oncologists and nine oncology pharmacists from one academic medical center and two community hospitals in Pennsylvania. Barriers to the use of preemptive PGx testing to guide chemotherapy dosing mapped to four CFIR domains: intervention characteristics, outer setting, inner setting, and characteristics of individuals. The most prominent themes included 1) a limited evidence base, 2) a cumbersome and lengthy testing process, and 3) a lack of insurance coverage for preemptive PGx testing. Additional barriers included clinician lack of knowledge, difficulty remembering to order PGx testing for eligible patients, challenges with PGx test interpretation, a questionable impact of preemptive PGx testing on clinical care, and a lack of alternative therapeutic options for some patients found to have actionable PGx variants.ConclusionsSuccessful adoption of preemptive PGx-guided chemotherapy dosing in patients with gastrointestinal malignancies will require a multifaceted effort to demonstrate clinical effectiveness while addressing the contextual factors identified in this study.

Government funds research to assess value of widespread pre-emptive pharmacogenetic testing

The UK government has awarded researchers more than £400,000 to assess the clinical value of routine pharmacogenetic testing that would allow prescribers to know in advance how someone is likely to respond to medication. Researchers at the University of Manchester are recruiting 646 people, who will be tested for genetic differences related to how they […]

The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia - a single center experience

Introduction/Objective. Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute lymphoblastic leukemia (ALL). By destabilizing microtubules, VCR arrests cells in metaphase, inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal transport, which leads to VCR-induced peripheral neuropathy (VIPN). This study aimed to investigate the association of five variants in pharmacogenes involved in VCR metabolism with VIPN in Serbian ALL children. We also wanted to discover candidate pharmacogenomic markers of VIPN in Serbian population. Methods. PCR and sequencing-based methodology was used to detect variants in CYP3?5, CEP72, ACTG1, MIR3117, and MIR4481 genes. Statistical analyses were performed for investigating their association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17 pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency distribution for the European population were extracted from public databases. Results. During the treatment, 17.86% of patients developed VIPN. Association analyses have shown that none of the genetic variants contributed to the occurrence of VIPN in our study. Population pharmacogenomics study did not reveal valid candidate pharmacovariants for VIPN. Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable presently. Conclusion. More comprehensive approaches are needed to identify the panel of genes that could explain the VIPN development after VCR administration in ALL patients. Utilizing better designed genome-wide association studies and more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive tests of VIPN to individualize therapy for ALL in children.

Current status and future outlooks on therapeutic drug monitoring of fluorouracil

Introduction : Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied. Areas covered : This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine. Expert opinion : New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Pre-emptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing

Purpose:The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Preemptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.Methods:In this report, we compare and contrast implementation strategies for preemptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.Results:We found that while preemptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Lastly, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for preemptive PGx testing remain low.Conclusion:These findings should inform the establishment of future implementation efforts at institutions considering a preemptive PGx testing program.

Pharmacist-guided pre-emptive pharmacogenetic testing in antidepressant therapy (PrePGx): study protocol for an open-label, randomized controlled trial

BackgroundIt is known that only 50% of patients diagnosed with major depressive disorders (MDD) respond to the first-line antidepressant treatment. Accordingly, there is a need to improve response rates to reduce healthcare costs and patient suffering. One approach to increase rates of treatment response might be the integration of pharmacogenetic (PGx) testing to stratify antidepressant drug selection. The goal of PGx assessments is to identify patients who have an increased risk to experience adverse drug reactions or non-response to specific drugs. Especially for antidepressants, there is compiling evidence on PGx influencing drug exposure as well as response.MethodsThis study is an open-label, randomized controlled trial conducted in two study centers in Switzerland: (1) the Psychiatric Clinic of Solothurn and (2) the Private Clinic Wyss in Münchenbuchsee. Adult inpatients diagnosed with a unipolar moderate or severe depressive episode are recruited at clinic admission and are included in the study. If the adjustment to a new antidepressant pharmacotherapy is necessary, the participants are randomized to either Arm A (intervention group) or Arm B (control group). If no new antidepressant pharmacotherapy is introduced the participants will be followed up in an observational arm. The intervention is the service of pharmacist-guided pre-emptive PGx testing to support clinical decision making on antidepressant selection and dosing. As a comparison, in the control group, the antidepressant pharmacotherapy is selected by the treating physician according to current treatment guidelines (standard of care) without the knowledge of PGx test results and support of clinical pharmacists. The primary outcome of this study compares the response rates under antidepressant treatment after 4 weeks between intervention and control arm.DiscussionThe findings from this clinical trial are expected to have a direct impact on inter-professional collaborations for the handling and use of PGx data in psychiatric practice.Trial registrationClinicalTrials.govNCT04507555. Registered on August 11, 2020. Swiss National Clinical Trials Portal SNCTP000004015. Registered August 18, 2020.

Farmacogenetische tests in de Belgische zorg: (hoe) beginnen we eraan?

Pharmacogenetic tests in Belgian care: (how) do we get started? Personalized medicine attempts to take all the information about an individual into account, and this also includes characteristics that differ from the presumed ‘average patient’. This approach includes pharmacogenetics, where the influence of genetic variation in various biomolecules on drug response is studied. By performing preemptive pharmacogenetic testing, drug therapies can be optimized, and serious side effects can be avoided. In order to implement pharmacogenetic testing in practice, some hurdles still need to be overcome. For example, scientific information needs to be translated into practical clinical guidelines that are applicable in the local context and reimbursement issues also need to be resolved. In this paper, a current list of gene-drug interactions is presented that could be prioritized during the implementation process in Belgium. The list only contains clinically relevant interactions for which there is sufficient scientific evidence. In addition, a tool is described that takes into account the drug consumption in a specific healthcare environment, to prioritize the most interesting gene-drug interactions. International implementation initiatives show that the obstacles are surmountable. It is therefore time to start a dialogue on accelerating the implementation of pharmacogenetic testing in Belgium. We hope that this prioritized list, together with a discussion of some hurdles that need to be overcome, can inform this debate.

Thiopurine-induced myelotoxicity in patients with acute leukemia and benefits of preemptive pharmacogenetic testing prior to 6-mercaptopurine prescription

Mercaptopurine (МР) is a key element of the maintenance therapy of acute leukemias. Different amounts of active and toxic metabolites can be synthesized in patients who are receiving the same doses of the drug due to pharmacokinetic differences. This contributes to the unequal drug tolerability and the need of dose adjustment. For a long time, the only tool for adjusting 6-MP dose was the level of leukocytes and granulocytes in the peripheral blood. With the understanding of genetic factors affecting the metabolism of 6-MP and development of next-generation sequencing technology, clinical guidelines for thiopurine dosing based on a pharmacogenetic approach have been emerged. In this article, we report two patients belonging to a small ethnic group in Russia with abnormal 6-MP toleration and substantiate the advantages of a personalized, pharmacogeneticallybased approach to 6-MP administration. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

Feasibility of preemptive pharmacogenetic testing in colorectal cancer patients within a community oncology setting.

Pharmacogenetics, in hand with precision medicine in oncology, represents an opportunity to holistically tailor a patient's treatment regimen using both somatic and germline variants to improve efficacy and decrease toxicity. Colorectal cancer patients represent a population with frequent use of fluoropyrimidine and irinotecan and are an ideal opportunity for implementation of preemptive pharmacogenetics as evidence supports pharmacogenetic testing for DPYD and UGT1A1 to reduce fluoropyrimidine and irinotecan toxicities. This was a single arm proof-of-concept study at a large community-based health system. Participants provided samples for pharmacogenetic testing via an external vendor prior to chemotherapy initiation and an oncology pharmacist was responsible for pharmacogenetic interpretation and pharmacogenetic-guided therapeutic recommendation to the treating provider. A total of 24 (60%) participants had a UGT1A1 variant. All participants (100%) were DPYD*1/*1. Results were available and interpreted for 29/40 (72.5%) participants prior to scheduled chemotherapy initiation (p value <0.014). Of the participants whose results were available in 5 weekdays or less (n = 23), 20 (87%) were communicated with the treating provider prior to scheduled chemotherapy administration. A total turnaround time of 5 days or less was significantly associated with PGx feasibility in a community-based oncology clinic (p = 0.03). In conclusion, we were able to show that implementation of preemptive pharmacogenetic testing into a community oncology clinic with results interpretation available prior to scheduled initiation of chemotherapy was feasible. As pharmacogenetic testing in oncology expands, pharmacists should be prepared to optimize supportive medication regimens as well as chemotherapy with pharmacogenetic results.

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.

Clinician perspectives on preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies.

54 Background: Pharmacogenetic (PGx) testing for germline variants in the DPYD and UGT1A1 genes can be used to guide fluoropyrimidine and irinotecan dosing, respectively. Despite the known association between PGx variants and chemotherapy toxicity, preemptive testing prior to chemotherapy initiation is rarely performed in routine practice. Methods: We conducted a multi-site mixed-methods study to understand clinician attitudes toward PGx testing and to identify facilitators and barriers to using preemptive testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. Each participant completed a demographic survey and semi-structured interview informed by the Consolidated Framework for Implementation Research. Interviews were analyzed using a modified grounded theory approach. Results: A total of 16 medical oncologists and 9 oncology pharmacists from one academic medical center and two community hospitals participated. Fifteen (60%) participants reported feeling comfortable or very comfortable with interpreting PGx test results. While clinicians expressed generally favorable attitudes toward PGx testing, many were hesitant to use it to preemptively guide chemotherapy dosing due to a perceived lack of evidence for this practice. They cited a lack of consensus chemotherapy dosing recommendations in response to PGx test results, as well as concerns about decreased drug efficacy, especially in patients treated with curative intent. Additional barriers included 1) a low prevalence of actionable PGx variants; 2) lengthy PGx test turnaround time; 3) concerns about testing costs and lack of insurance coverage; and 4) burdensome integration of PGx testing into clinical workflows. The electronic health record emerged as a potential tool for the unobtrusive integration of PGx testing into clinical practice–suggested applications included default PGx test orders for eligible patients, discrete reporting of PGx variant results, and clinical decision support to guide subsequent chemotherapy dosing. Conclusions: Successful adoption of preemptive PGx-guided chemotherapy dosing in patients with gastrointestinal malignancies will require a multi-level effort to demonstrate clinical effectiveness while addressing the contextual factors identified in this study. The electronic health record should be explored as a tool to integrate PGx testing into routine practice.

Estimating the potential impact of implementing pre-emptive pharmacogenetic testing in primary care across the UK.

Pharmacogenetics (PGx) in the UK is currently implemented in secondary care for a small group of high-risk medicines. However, most prescribing takes place in primary care, with a large group of medicines influenced by commonly occurring genetic variations. The goal of this study is to quantitatively estimate the volumes of medicines impacted by implementation of a population-level, pre-emptive pharmacogenetic screening programme for nine genes related to medicines frequently dispensed in primary care in 2019. A large community pharmacy database was analysed to estimate the national incidence of first prescriptions for 56 PGx drugs used in the UK for the period 1 January-31 December 2019. These estimated prescription volumes were combined with phenotype frequency data to estimate the occurrence of actionable drug-gene interactions (DGI) in daily practice in community pharmacies. In between 19.1 and 21.1% (n=5 233 353-5 780 595) of all new prescriptions for 56 drugs (n=27 411 288 new prescriptions/year), an actionable drug-gene interaction (DGI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group and/or the Clinical Pharmacogenetics Implementation Consortium. In these cases, the DGI would result in either increased monitoring, guarding against a maximum ceiling dose or an optional or immediate drug/dose change. An immediate dose adjustment or change in drug regimen accounted for 8.6-9.1% (n=2 354 058-2 500 283) of these prescriptions. Actionable drug-gene interactions frequently occur in UK primary care, with a large opportunity to optimise prescribing.