Preemptive Testing Research Articles

TPMT and NUDT15 testing for thiopurine therapy: A major tertiary hospital experience and lessons learned.

Variants in thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are associated with an accumulation of cytotoxic metabolites leading to increased risk of drug-related toxicity with standard doses of thiopurine drugs. We established TPMT and NUDT15 genetic testing for clinical use and evaluated the utilization, service outcomes and potential value of multi-gene PGx testing for 210 patients that underwent pharmacogenetics (PGx) testing for thiopurine therapy with the aim to optimize service delivery for future prescribing. The test was most commonly ordered for Gastroenterology (40.0%) and Neurology (31.4%), with an average turnaround time of 2 days. Following testing, 24.3% patients were identified as intermediate or poor metabolizers, resulting in 51 recommendations for a drug or dose change in thiopurine therapy, which were implemented in 28 (54.9%) patients. In the remaining patients, 14 were not adjusted and 9 had no data available. Focusing on drug gene interactions available for testing in our laboratory, multi-gene PGx results would present opportunities for treatment optimization for at least 33.8% of these patients who were on 2 or more concurrent medications with actionable PGx guidance. However, the use of PGx panel testing in clinical practice will require the development of guidelines and education as revealed by a survey with the test providers. The evaluation demonstrated successful implementation of single gene PGx testing and this experience guides the transition to a pre-emptive multi-gene testing approach that provides the opportunity to improve clinical care.

Protection of vaccination versus hybrid immunity against infection with COVID-19 Omicron variants among Health-Care Workers

Background aimThe Omicron COVID-19 variants BA.1* and BA.2* evade immune system leading to increased transmissibility and breakthrough infections. We aim to test the hypothesis that immunity achieved post COVID-19 infection combined with vaccination (hybrid immunity), is more effective against Omicron infection than vaccination alone in a health-care setting. MethodsData on regular pre-emptive PCR testing from all Health-Care Workers (HCWs) at Laiko University Hospital from 29th December 2020, date on which the national COVID-19 immunization program began in Greece, until 24th May 2022, were retrospectively collected and recorded. The infection rate was calculated after December 21st, 2021, when Omicron was the predominant circulating variant in Greece, as the total number of infections (positive PCR COVID-19 test regardless of symptoms) divided by the total person-months at risk. ResultsOf 1,305 vaccinated HCWs who were included in the analysis [median age of 47 (IQR: 36, 56) years, 66.7 % women], 13 % and 87 % had received 2 or 3 vaccine doses (full and booster vaccination), respectively. A COVID-19 infection had occurred in 135 of 1,305 of participants prior to Omicron predominance. Of those 135 HCWs with hybrid immunity only 13 (9.6 %) were re-infected. Of the 154 and 1,016 HCWs with full and booster vaccination-induced immunity, respectively, 71 (46.1 %, infection rate 13.4/100 person-months) and 448 (44.1 %, infection rate 12.2/100 person-months) were infected during the follow up period. No association between gender or age and COVID-19 infection was found and none of the participants had a severe infection or died. ConclusionsHybrid immunity confers higher protection by almost 5-fold compared to full or booster vaccination for COVID-19 infection with the Omicron variant among HCWs who are at high risk of exposure. This may inform public health policies on how to achieve optimal immunity in terms of the timing and mode of vaccination.

Thiopurine S-Methyltransferase Polymorphisms Predict Hepatotoxicity in Azathioprine-Treated Patients with Autoimmune Diseases.

Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in Azathioprine (AZA) metabolization. Although studies have discussed the association between the TPMT polymorphisms and myelosuppression, the data about the relationship between TPMT genotypes and hepatoxicity in Asian patients remain limited. This study investigated the correlation between TPMT polymorphisms and AZA-related hepatotoxicity. This study enrolled the patients who had prior exposure to AZA from the Taichung Veterans General Hospital (TCVGH)-Taiwan Precision Medicine Initiative (TPMI) cohort. Genetic variants were determined using a single nucleotide polymorphism (SNP) array. Participants were accordingly categorized into normal metabolizer (NM) and non-normal metabolizer (non-NM) groups. From the TCVGH-TPMI cohort, we included 50 TPMT non-NM patients, including 1 poor metabolizer (PM), 49 intermediate metabolizers (IMs), and 1000 NM patients. The non-NM genotype was associated with hepatotoxicity compared with the NM genotype (hazard ratio (HR): 3.85, 95% confidence interval (CI): 1.83–8.10). In the non-NM group, the 3-year cumulative incidence of hepatotoxicity was higher than that in the NM group at 8.5% in the first year and 18.6% in the second and third years (p < 0.001). A TPMT non-NM genotype was associated with the occurrence of hepatotoxicity following AZA therapy. Preemptive testing helps individualize AZA therapy by minimizing the risk of hepatotoxicity.

The First Evaluation of Proteinase K-Resistant Prion Protein (PrPSc) in Korean Appendix Specimens.

Background and Objectives: Prion diseases are fatal neurodegenerative disorders caused by the abnormal proteinase K-resistant prion protein (PrPSc). Since variant Creutzfeldt–Jakob disease (CJD) was first reported in the United Kingdom (UK) in 1996, the occurrence of variant CJD has been reported in over 10 countries. To date, variant CJD has not been reported in Korea. However, the E211K somatic mutation in the prion protein gene (PRNP), which is related to bovine spongiform encephalopathy (BSE), was reported in Korean Holstein cattle, and atypical BSE, which is supposed to be sporadic BSE, has been occurring in many countries, including Japan and the USA. These results suggest that BSE may occur naturally in Korea. Thus, we performed a preemptive PrPSc test in appendix specimens to diagnose variant CJD in a Korean population. Materials and Methods: In the present study, we investigated CJD-related mutations and polymorphisms of the PRNP gene and carried out an examination on PrPSc in appendix specimens of Korean patients after appendectomy. Results: In all Korean appendix specimens tested, PrPSc bands were not detected. Conclusion: To the best of our knowledge, this was the first evaluation of PrPSc in Korean appendix specimens.

Evaluation of the Public Health Emergency Response to the COVID-19 Pandemic in Daegu, Korea During the First Half of 2020.

ObjectivesThis study evaluated the response in Daegu, Korea to the first wave of the coronavirus disease 2019 (COVID-19) pandemic according to a public health emergency response model.MethodsAfter an examination of the official data reported by the city of Daegu and the Korea Centers for Disease Control and Prevention, as well as a literature review and advisory meetings, we chose a response model. Daegu’s responses were organized into 4 phases and evaluated by applying the response model.ResultsIn phase 1, efforts were made to block further transmission of the virus through preemptive testing of a religious group. In phase 2, efforts were concentrated on responding to mass infections in high-risk facilities. Phase 3 involved a transition from a high-intensity social distancing campaign to a citizen participation–based quarantine system. The evaluation using the response model revealed insufficient systematic preparation for a medical surge. In addition, an incorporated health-related management system and protection measures for responders were absent. Nevertheless, the city encouraged the participation of private hospitals and developed a severity classification system. Citizens also played active roles in the pandemic response by practicing social distancing.ConclusionsThis study employed the response model to evaluate the early response in Daegu to the COVID-19 pandemic and revealed areas in need of improvement or maintenance. Based on the study results, creation of a systematic model is necessary to prepare for and respond to future public health emergencies like the COVID-19 pandemic.

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.

#45 Antibiotic Exposure and Risk of Cytomegalovirus Viremia Among Pediatric Hematopoietic Stem Cell Transplant Recipients at a Single Institution

Abstract Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HCT), and antibiotic exposure after HCT is increasingly recognized as a risk for negative clinical outcomes. Recent studies identified an association between receipt of antibiotics with an anaerobic spectrum of activity and infection with cytomegalovirus (CMV) after HCT in adults. We sought to evaluate the association between anaerobic antibiotic exposure and CMV viremia in a well-characterized cohort of pediatric HCT recipients. Method We conducted a single-center retrospective cohort study of HCT recipients &amp;lt;18 years of age who underwent HCT at Duke University between 2000 and 2016. Routine pre-emptive surveillance testing for CMV was performed; CMV viremia was defined as a positive whole blood hybrid capture CMV DNA assay or quantitative plasma CMV PCR. We used log-logistic regression to evaluate associations between anaerobic antibiotic exposure (vancomycin, metronidazole, meropenem, piperacillin-tazobactam) and CMV viremia-free survival at 100 days after HCT. The first model considered anaerobic antibiotic exposure in the first 14 days after HCT as a binary variable. The second model considered anaerobic antibiotic exposure in the first 100 days as a time-varying variable; once a subject was exposed to a specific antibiotic, they were considered exposed for the remainder of the study period. Both models adjusted for year of HCT, age, race, HCT type and donor cell source, underlying diagnosis, conditioning regimen, CMV serostatus, and treatment for graft-versus-host-disease. Results Among 966 children, median (interquartile range) age was 6.5 (3.1, 11.5) years. Hematologic malignancy was the indication for transplantation in 417 (43%) subjects. Of 770 allogeneic HCT, 566 (74%) were from an umbilical cord blood donor and 204 (26%) were from a bone marrow donor. The majority of HCT were recipient CMV-seronegative and donor CMV-seronegative (R-/D-; 537, 56%), with 24 (2%) R-/D+, 270 (28%) R+/D-, and 135 (14%) R+/D+ transplants. Within the first 100 days after HCT, 692 (72%) children received vancomycin, 363 (38%) received metronidazole, 231 (24%) received meropenem, and 121 (13%) received piperacillin-tazobactam. Exposure to vancomycin (OR=0.86; 95% CI: 0.59, 1.26), metronidazole (OR=0.76; 95% CI: 0.53, 1.10), meropenem (OR=1.19; 95% CI: 0.74, 1.90), or piperacillin-tazobactam (OR=1.03; 95% CI: 0.55, 1.92) in the first 14 days after HCT was not associated with the risk of CMV viremia-free survival at 100 days. Similarly, we found no increased risk of CMV viremia with anaerobic antibiotic exposure in the first 100 days after HCT (vancomycin OR=0.90; 95% CI: 0.60, 1.34; metronidazole OR=0.80; 95% CI: 0.53, 1.21; meropenem OR=0.98; 95% CI: 0.60, 1.62; piperacillin-tazobactam OR=0.69; 95% CI: 0.38, 1.23). Conclusion In this study of pediatric HCT recipients, we did not find evidence of an association between anaerobic antibiotic exposures and CMV viremia risk. However, future pediatric and adult studies are warranted to evaluate this previously reported association in other populations, including studies evaluating for a possible role of the gut microbiome in modifying CMV viremia risk after HCT.

Advancing Pharmacogenomics from Single-Gene to Preemptive Testing.

Pharmacogenomic testing can be an effective tool to enhance medication safety and efficacy. Pharmacogenomically actionable medications are widely used, and approximately 90-95% of individuals have an actionable genotype for at least one pharmacogene. For pharmacogenomic testing to have the greatest impact on medication safety and clinical care, genetic information should be made available at the time of prescribing (preemptive testing). However, the use of preemptive pharmacogenomic testing is associated with some logistical concerns, such as consistent reimbursement, processes for reporting preemptive results over an individual's lifetime, and result portability. Lessons can be learned from institutions that have implemented preemptive pharmacogenomic testing. In this review, we discuss the rationale and best practices for implementing pharmacogenomics preemptively.

Avoidance of cutaneous adverse drug reactions induced by antiepileptic drugs based on pharmacogenomics.

Pharmacogenomics (PGx) is a research area aimed at identifying genetic factors that are associated with drug responses, including drug efficacy, adverse drug reactions, and the appropriate drug dosage on a case-to-case basis. To promote the clinical implementation of PGx testing, which is currently of limited use in clinical practice, recent research has focused on providing reliable evidence for its clinical utility. In neurology, psychiatry, and neurosurgery, several human leukocyte antigen (HLA) alleles have been reportedly associated with cutaneous adverse drug reactions (cADRs) induced by antiepileptic drugs, which significantly carry the risk of developing cADRs. Prior to using antiepileptic drugs such as carbamazepine and lamotrigine, which are prone to cause severe cADRs, preemptive HLA genetic testing and therapeutic interventions such as drug selection and dosage adjustment based on the results of the tests can reduce the incidence of cADRs in the population before the initiation of treatment.

Impact of pre-emptive rapid testing for glucose-6-phosphate dehydrogenase deficiency prior to rasburicase administration at a tertiary care centre: A retrospective study.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, can cause acute haemolysis resulting from exposure to certain medications, chemicals, infections and fava beans. Rasburicase, used to manage elevated uric acid levels in the oncologic emergency of tumour lysis syndrome, is one such drug. The US Food and Drug Administration (FDA) recommends testing of G6PD status prior to rasburicase administration for patients at higher risk for G6PD deficiency. We performed a retrospective chart review of all oncology patients for whom a semi-quantitative biochemical test for detecting G6PD deficiency was performed prior to rasburicase administration over a 2.5-year period, in a large academic metropolitan hospital. We identified 16 out of 260 tested individuals as G6PD-deficient (6.1%), including six females. On average, test results were electronically available to health care providers within 4hours of sample collection, with most results available within 2-3hours. Four G6PD-deficient patients developed elevated uric acid levels. Two of the G6PD-deficient patients were treated with rasburicase, and subsequently developed haemolysis, which was appropriately managed. In summary, by providing information about G6PD status with a rapid turnaround time, we have taken a significant step towards personalized medicine in our institution. In spite of the test implementation, two out of four G6PD-deficient patients, who were no longer candidates for rasburicase use, still received the drug, highlighting the need for improved provider education.

Clinical implications of germline variations for treatment outcome and drug resistance for small molecule kinase inhibitors in patients with non-small cell lung cancer.

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

Automated Pharmacogenomic Reports for Clinical Genome Sequencing

Clinical laboratories offering genome sequencing have the opportunity to return pharmacogenomic findings to patients, providing the added benefit of preemptive testing that could help inform medication selection or dosing throughout the lifespan. Implementation of pharmacogenomic reporting must address several challenges, including inherent limitations in short-read genome sequencing methods, gene and variant selection, standardization of genotype and phenotype nomenclature, and choice of guidelines and drugs to report. An automated pipeline, lmPGX, was developed as an end-to-end solution that produces two versions of a pharmacogenomic report, presenting either Clinical Pharmacogenetics Implementation Consortium or US Food and Drug Administration guidelines for 12 genes. The pipeline was validated for performance using reference samples and pharmacogenetic data from the Genetic Testing Reference Materials Coordination Program. To determine performance and limitations, lmPGX was compared with three additional publicly available pharmacogenomic pipelines. The lmPGX pipeline offers clinical laboratories an opportunity for seamless integration of pharmacogenomic results with genome reporting.

Opportunity for pharmacogenomic testing in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing before initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. The aim of this study is to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patients with CF. We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug-gene pairs that can be used to guide therapy. We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 and May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. Patients with CF have high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing.

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.

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.

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 […]

Pharmacogenetics Implementation in Primary Care

Pharmacogenetics is being considered as a pre-emptive test for the National Health Service in the United Kingdom. Primary care is a key clinical service for the use of this technology due to the large number of prescriptions prescribed in this setting. Given the volume of prescribing and the prevalence of pharmacogenetic variants an average GP will be using pharmacogenetics approximately 12 times per week. The current high workload in primary care means that a time of only a minute or two at most is available for the physician to use this new information. Pharmacogenetics is only one data point in identifying drug options for a patient. In determining those options physicians also take into account drug-drug, drug-condition, drug-liver and drug-renal potential interactions. Clinical Decision Support Systems exist that use pharmacogenetic and other information to help identify safer and more effective medication options for an individual.

Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor.

Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR’s clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient’s quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into individualized therapies. In this review, we discussed the potential associations between genetic variants in genes contributing to the pharmacokinetics/pharmacodynamics of VCR and VIPN incidence and severity in patients with acute lymphoblastic leukemia. Of note, genetic variants in the CEP72 gene have great potential to be translated into clinical practice. Such a genetic biomarker may help clinicians diagnose VIPN earlier. Besides, genetic variants in other genes, such as CYP3A5, ABCB1, ABCC1, ABCC2, TTPA, ACTG1, CAPG, SYNE2, SLC5A7, COCH, and MRPL47, have been reported to be associated with the VIPN, but more evidence is needed to validate the findings in the future. In fact, a variety of complex factors jointly determine the VIPN. In implementing precision medicine, the combination of genetic, environmental, and personal variables, along with therapeutic drug monitoring, will allow for a better understanding of the mechanisms of VIPN, improving the effectiveness of VCR treatment, reducing adverse reactions, and improving patients’ quality of life.

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.