Use Of Pharmacogenetic Testing Research Articles

Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing.

Clinical pharmacists’ knowledge, attitude, perception, and beliefs about the role of pharmacogenetic testing for genes polymorphisms when prescribing mercaptopurine

BackgroundSingle nucleotide polymorphisms in the gene encoding proteins involved in mercaptopurine metabolism can influence drug efficacy and safety. This study aims to assess clinical pharmacists’ knowledge about mercaptopurine-related genes and their polymorphisms and investigate their attitudes, perceptions, and beliefs about the need for and importance of pharmacogenetic testing for mercaptopurine. MethodsA cross-sectional descriptive study was conducted among oncology/hematology clinical pharmacists in Saudi Arabia using an online-questionnaire developed by experts in the field. The questionnaire consists of four-sections exploring clinical pharmacists’ knowledge, attitudes, perceptions, and beliefs about the importance of gene testing and genes polymorphism when prescribing mercaptopurine. Descriptive statistics were used to analyze the data in the study. ResultsA total of 41 oncology/hematology clinical pharmacists responded to the survey invitation. Almost half of them had more than 10 years of work experience, but only 17 % of them received formal training in pharmacogenetics. The overall level of knowledge about pharmacogenetics among participants was low, with a mean score of 2.8 points (1.7) out of 8 items. However, around 76 % agreed that it is important to perform pharmacogenetic screening prior to prescribing mercaptopurine, and almost 93 % state that it will influence their dosage recommendation. Most of the participants had a good perception (95.1 %) of their role in genetic testing for medication selection, dosing, and monitoring; however, about 10 % of surveyed pharmacists reported not being completely responsible about recommending pharmacogenetic testing. The surveyed pharmacists had a good belief in the importance of pharmacogenetic testing and their overall attitude was positive toward the use of pharmacogenetic testing, with emphasis on the importance of training on the proper assessment and interpretation of pharmacogenetic tests. ConclusionsPharmacists demonstrated good perception and positive attitude toward pharmacogenetic testing, despite the low level of knowledge and limited formal training. Thus, more attention to developing national guidelines on pharmacogenetic testing is warranted to ensure successful pharmacogenetic testing implementation.

Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

The role of pharmacogenetics in the treatment of major depressive disorder: a critical review.

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

Providers' Use of Pharmacogenetic Testing to Inform Antidepressant Prescribing: Results of Qualitative Interviews.

Pharmacogenetic testing (PGx) for patients experiencing depression has been associated with modest improvements in symptoms. However, little is known about providers' use of PGx, including how and for whom providers use the test results in clinical decision making. In this article, results from qualitative interviews on the experience of providers participating in a pragmatic trial of PGx are described; implications of the providers' experiences are highlighted to inform future implementation of PGx. Interviews were conducted with providers participating in the trial (N=61) who treated veterans who had depression. Questions were informed by the Consolidated Framework for Implementation Research. A rapid analytic approach was used. Two main themes were identified: perceptions regarding which patients would likely benefit from PGx and approaches to using the test results in prescribing. Providers generally expressed positive experiences with using PGx results. However, the providers varied in application of the test results to clinical decision making regarding medications, were uncertain about how much to rely on the results, and differed in perceptions about which patients would benefit from PGx. To support future implementation, policies and procedures are needed, as well as mechanisms to support ongoing provider education on PGx.

Generalized Anxiety Disorder Therapy, Associated with Pronounced Side Effects, and Prospects for the Use of Pharmacogenetic Testing: Case report

New generation antidepressants (AD) are widely used as first-line treatment for generalized anxiety disorder (GAD) and considered safely than tricyclics. Some side effects of AD are transient and may disappear after few weeks of treatment, but potentially severe may persist for a long time or occur later. Cardiovascular disorders (abnormal heart rhythm, QT prolongation, arterial hypertension, orthostatic hypotension) are especially dangerous side effects. Genetic polymorphisms of the enzymes involved in the metabolism of antidepressants may be one of the causes of side effects development. The objective of this case report is to demonstrate that timely assessment of the risk of side effects using pharmacogenetic testing (PGx) could have influenced choice of an antidepressant, timely dose adjustment, avoiding ineffective appointments. Use of the PGx can help to optimize GAD pharmacotherapy, its introduction into clinical practice requires further research.

Mental Health Prescribers' Perceptions on the Use of Pharmacogenetic Testing in the Management of Depression in the Middle East and North Africa Region.

A wide variety of commercial pharmacogenetic (PGx) tools are available worldwide to guide treatment selection for depression based on individuals' genetic profiles. However, the use of genetic testing to inform psychiatric care has faced challenges due to the limited training and education for mental health clinicians. The aim of this study was to explore the knowledge, level of engagement, and perspectives on the use of PGx testing when making depression management decisions among practicing psychiatrists within the Middle East and North Africa (MENA) region. This is a qualitative study using semi-structured interviews. Consenting psychiatrists were interviewed through an online platform (SkypeTM or Microsoft TeamsTM). Interviews were audio recorded, transcribed, and thematically analyzed with the assistance of NVivo® software. Eighteen interviews from 12 countries have been conducted. Analysis of the current interviews produced five major themes including: (1) Overall perceptions and attitudes; (2) Knowledge and awareness; (3) Education, training, and professional experience; (4) Facilitators and barriers; and (5) Ethical dilemmas. These themes support the notion that there is limited, mostly basic, education, knowledge, and training regarding genetic testing in the management of depression, although there is significant interest and willingness in the part of prescribers to adopt this strategy in their practice. The findings of the study suggest that psychiatrists practicing in the MENA region appear to be interested in implementing PGx testing when managing people with depression. However, it is also important to recognize that this cannot be achieved unless more supporting strategies are implemented within their current health system environment.

459 Clinical Utility of Pharmacogenetic Tests When Prescribing Antidepressant Therapy for Depression, A Systematic Review and Meta-analysis of Randomised Controlled Trials

Abstract Introduction Pharmacogenetic testing when prescribing medicines has the potential to reduce harmful side effects, optimise treatment, and improve clinical outcomes. Depression is a major global disease burden with high economic costs and it’s becoming more prevalent (1). There is a growing number of clinical trials and reviews that support the use of pharmacogenetic testing for depression and more results are available from randomised controlled trials (RCTs) that were completed recently to warrant a new systematic review (2). Aim The aim was to evaluate the clinical utility of pharmacogenetic tests when prescribing antidepressant therapy for depression (including mild, moderate, and major depression) by comparing the remission rate, antidepressant response and adverse events from RCTs for the pharmacogenetic guided therapy group and the treatment as usual group (TAU) through a systematic review and meta-analysis. Methods The PICO inclusion criteria are adults with depression requiring antidepressant therapy for depression. The intervention is a pharmacogenetic gene test(s) and the comparator is usual treatment. The outcomes are depression remission, antidepressant response and adverse events. This research was undertaken between April and September 2022 by the main author (SJ). The second author (HA) peer reviewed the title/abstract screening, full text review, and the third author (PD) provided supervisory support. A systematic literature search was completed using Embase, Medline, Cochrane, and PubMed databases according to a published PROSPERO protocol. Articles published between 2000 - 2022 were eligible. Only RCTs that had TAU as the comparator were included. Bias and quality assessments were carried out using the RoB 2 tool. Studies with a high risk of bias were excluded. Heterogeneity was calculated using I2. A random effects model meta-analysis was conducted using RevMan. Results In total, 520 articles were retrieved at first search (excluding duplicates) and seven double-blinded (rater and patient blinded) RCTs were identified that met the full inclusion and exclusion criteria. The RCTs were based in North America (5), Australia (1) and Europe (1). The meta-analysis revealed the remission rate was greater for pharmacogenetic guided groups compared to the TAU groups, pooled risk ratio (RR) = 1.54 (95% CI 1.07-2.21, p = 0.02). For the response rate, results from 6 double blinded RCTs which measured this had a pooled RR= 1.23 (95% CI 0.95-1.59, p = 0.11) which indicates a greater (but not statistically significant) response rate in the pharmacogenetic guided group. Conclusion A limitation of this study is that it showed improvement in remission but not response rate, which is potentially due to response data missing from one of the seven pooled studies. Pharmacogenetic tests might have the potential to improve remission and response rates for antidepressant therapy compared to treatment as usual. However, further studies in the UK are warranted to help determine whether pharmacogenetic tests should be used in an NHS setting.

PHARMACOGENETICS IN CHILD AND ADOLESCENT PSYCHIATRY: A CLINICAL UPDATE

AACAP has recently called for caution regarding the use of pharmacogenetic testing to guide mental health care. This Symposium will review the available evidence examining the moderating effects of genetic variants on psychotropic efficacy and tolerability.

Clinical Use of Pharmacogenetic Tests: An Official Statement Issued by The Japanese Society of Clinical Pharmacology and Therapeutics

Clinical Use of Pharmacogenetic Tests: An Official Statement Issued by The Japanese Society of Clinical Pharmacology and Therapeutics

Pharmacogenetic testing among patients with depression in a US managed care population.

Actionable drug–gene pairs relevant to depression treatment include CYP2D6 and CYP2C19 with specific antidepressants. While clinical use of pharmacogenetic testing is growing, little is known about pharmacogenetic testing for depression treatment in managed care. We determined the incidence of single‐gene CYP2D6 and CYP2C19 testing following a new depression episode among US managed care patients, and described characteristics and antidepressant use of patients receiving tests. We used paid medical and pharmacy claims for patients from commercial health plans in the US. For adult patients with a new depression episode from January 1, 2013 to June 30, 2018, we identified covered claims for single‐gene CYP2D6 and CYP2C19 pharmacogenetic tests and antidepressant fills. Fewer than 1% (n = 1795) of the depressed cohort (n = 438,534) received a single‐gene CYP2D6 or CYP2C19 test through their insurance within 365 days of their earliest depression episode. The percentage of patients who received a test nearly tripled from 0.2% in 2013 to 0.5% in 2014 before plateauing at 0.4% from 2014 to 2017. Among the patients who received a single‐gene CYP2D6 or CYP2C19 test and filled an antidepressant within 365 days of their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result. Our findings describe the use of antidepressants before and after pharmacogenetic testing, which is clinically relevant as pharmacogenomic testing becomes more common in clinical practice. Our study also emphasizes the need for procedure and billing codes that capture multiple‐gene panel tests to be more widely implemented in administrative databases.

Genetic Risk Factors for Adverse Drug Reactions

The use of medicines may in some cases be associated with the development of drug-induced diseases (DIDs) аnd other adverse drug reactions (ADRs), which leads to an increase in morbidity/mortality rates, and/or symptoms forcing a patient to seek medical attention or resulting in hospitalisation. ADRs may develop due to changes in a patient’s genotype, which entail an inadequate pharmacological response. The aim of the study was to analyse and summarise literature data on genetic risk factors that cause DIDs аnd other ADRs. It was shown that the polymorphism of genes encoding enzymes of drug metabolism (CYP, UGT, NAT, TPMT, EPHX, GST, etc.) or carriers (transporters) of drugs (P-gp, BCRP, MRP, OATP, OCT, etc.) can change the pharmacokinetics of drugs, affecting their activity. Polymorphism of RYR1, CACNA1S, MT-RNR1, VKORC1, and other genes encoding receptors targeted by drugs, and human leukocyte antigen (HLA) gene, may affect drug pharmacodynamics by modifying drug targets or changing the sensitivity of biological pathways to pharmacological effects of medicines. Changes in drug pharmacokinetics and pharmacodynamics may cause DIDs аnd other ADRs. The use of pharmacogenetic tests will allow a personalised approach to patients’ treatment and prevention or timely detection of potential ADRs during therapy. Before prescribing some medicines, clinicians should use recommendations on their dosing based on pharmacogenetic tests, which are posted on the official websites of Pharmacogenomics Research Network (PGRN), Pharmacogenomics Knowledgebase (PharmGKB), and Clinical Pharmacogenetics Implementation Consortium (CPIC). The results of ongoing clinical studies on the effect of gene polymorphism on drug safety will soon allow for higher personalisation of the choice of pharmacotherapy and prevention of many ADRs, including DIDs.

Pharmacogenomics in Cytotoxic Chemotherapy of Cancer.

Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.

The use of pharmacogenetic testing in psychiatry.

Psychiatric pharmacogenetic testing is commonly used by providers in primary care and mental health settings. The purpose of this article is to describe the extent to which psychiatric pharmacogenetic testing supports clinical practice. human leukocyte antigen (HLA)-A and HLA-B should be tested before initiating carbamazepine and oxcarbazepine due to risk of serious skin reactions. For psychotropic medications metabolized through the liver, limited evidence suggests testing for variation in metabolism through CYP2D6 and CYP2D19. For specific medication and genotype-phenotype variations, guidance through the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the International Society of Psychiatric Genetics (ISPG) should be reviewed. Commercial tests interpret this information differently and should not be used for broad guidance. Clinicians should follow current guidelines from professional bodies such as CPIC or ISPG and test for HLA-A or HLA-B before initiating carbamazepine or oxcarbazepine. Evidence is limited for psychiatric pharmacogenetic testing. Clinicians should continue to follow best practice and clinical practice guidelines.

Perspectives on the Clinical Use of Pharmacogenetic Testing in Late-Life Mental Healthcare: A Survey of the American Association of Geriatric Psychiatry Membership

To assess perspectives on pharmacogenetic (PGx) testing among members of the American Association of Geriatric Psychiatry (AAGP). Cross-sectional survey. Members of the AAGP. Anonymous web-based survey consisting of 41 items covering experiences, indications, barriers, facilitators and ethical, legal and social implications for PGx testing. A total of 124 surveys were completed (response rate=13%). Most respondents (60%) had used PGx testing but an equal proportion (58%) was uncertain about the clinical usefulness of PGx testing in late-life mental health. Despite self-reported confidence in the ability to order and interpret PGx testing, 60% of respondents felt there was not enough clinical evidence for them to use PGx testing in their practice. This was compounded by uncertainties related to their ethical obligation and legal liability when interpreting and using (or not using) PGx testing results. Respondents strongly affirmed that clinical and legal guidelines for PGx testing in older adults are needed and would be helpful. The findings suggest additional PGx research and physician education in late-life mental healthcare settings is required to reconcile uncertainties related to the clinical efficacy and ethico-legal aspects of PGx testing as well as address current knowledge barriers to testing uptake. These efforts would be further facilitated by the development of clinical practice guidelines to ensure equitable access to testing and standardized implementation of PGx-informed prescribing in older adults.

52.2 AN UPDATE ON GENE-MEDICATION INTERACTIONS RELEVANT TO PEDIATRIC PSYCHOPHARMACOTHERAPY

Pharmacogenetic studies of pediatric patients are scarce, but clinicians frequently obtain pharmacogenetic testing in children and adolescents. This presentation will review the influence of pharmacokinetic and pharmacodynamic genes on response to antidepressants in youth. A review of the evidence for key pharmacokinetic and pharmacodynamic genes that impact medication tolerability and response in youth will be provided. Specifically, recent studies from our group reporting how: 1) CYP2C19 influences sertraline and escitalopram tolerability; 2) pharmacodynamic genes encoding the serotonin transporter and receptor 2A, SLC6A4, and HTR2A, influence SSRI response; and 3) MTHFR and L-methylfolate do not influence response to antidepressants. Two large retrospective studies in pediatric patients with anxiety and/or depressive disorders reported how CYP2C19 influences response and tolerability to escitalopram (N = 248) and sertraline (N = 352). Another study in a similar population (N = 164) indicated that the response to fluoxetine was associated with SLC6A4 and HTR2A variants but not CYP2D6. One prospective study of patients with anxiety disorders (N = 26) demonstrated that CYP2C19, SLC6A4, and HTR2A were associated with escitalopram response trajectory. In a retrospective analysis of patients that had MTHFR genotyping (n = 292), 23% received L-methylfolate supplementation. Neither the MTHFR genotypes nor L-methylfolate supplementation influenced response to antidepressants. Pharmacogenes are associated with both response and tolerability in youth treated with antidepressants in retrospective studies. Child and adolescent psychiatrists should know the evidence behind these studies as they consider use of pharmacogenetic testing in their clinical practice.

A cross-sectional study of the relationship between CYP2D6 and CYP2C19 variations and depression symptoms, for women taking SSRIs during pregnancy.

Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical guidelines provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; however, they are based on evidence from non-pregnant cohorts. This study aimed to test the hypothesis that women with function-altering variants (increased, decreased, or no function) in these pharmacogenes, taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants are associated with normal SSRI metabolism. Comprehensive CYP2D6 and CYP2C19 genotyping using a range of methods, including gene copy number analysis, was performed as secondary analyses on two longitudinal cohorts of pregnant women (N= 83) taking the SSRIs paroxetine, citalopram, escitalopram, or sertraline. The Kruskal-Wallis test compared mean depression scores across four predicted metabolizer groups: poor (n= 5), intermediate (n= 10), normal (n= 53), and ultrarapid (n= 15). There were no significant differences between mean depression scores across the four metabolizer groups (H(3) = .73, p= .87, eta-squared = .029, epsilon-squared = .0089). This is the first study of the relationship in pregnancy between CYP2C19 pharmacogenetic variations and depression symptoms in the context of SSRI use. Findings from this initial study do not support the clinical use of pharmacogenetic testing for SSRI use during the second or third trimesters of pregnancy, but these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, especially as companies offering direct-to-consumer genetic testing expand their marketing efforts.

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network

PurposeA critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions. MethodsThe Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation. ResultsTwo pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression. ConclusionIGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.

The feasibility and potential role of pharmacogenetics to improve drug safety in patients with advanced cancers.

e22522 Background: Pharmacogenetics is the study of genetic variants that define drug metabolism and dosing requirements, response or toxicity. Knowledge regarding drug-drug interactions and individual variations in genes involved in drug metabolism is increasing. Since patients with cancer often take several drugs (polypharmacy), they have a higher risk of severe drug interactions. The FDA lists several pharmacogenetic biomarkers in drug labeling, including genetic variants that impact how certain medications are prescribed. The drugs listed span multiple medical applications, including but not limited to oncology, primary care, psychiatry, neurology, cardiology, and many more. Adverse drug reactions are a significant cause of morbidity and mortality, yet the use of pharmacogenetic testing has not yet become established as a routine in clinical practice. Herein we sought to study the feasibility of applied pharmacogenetics in a pilot drug safety program in patients with advanced cancer. Methods: We enrolled patients in a prospective single-center IRB approved study. Patients with advanced cancer on three or more drugs about to begin chemotherapy at the Hoag Family Cancer Institute were eligible. Informed consent was obtained from the study participants, and their samples were sent to a CLIA laboratory to conduct a 25-gene pharmacogenetics testing panel, which includes “major drug-metabolizing enzymes” CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5 as well as other genes with known drug implications. We recorded patients’ demographics and clinical information. In addition, participant’s drug lists were assessed for potential polypharmacy interactions. Results: We analyzed the results from 36 patients, 20 females and 16 males, enrolled between December 2017 and June 2020. Pharmacogenetics results from these patients showed that 61% (22 patients) had a variant with gene drug interaction indication. The most common variants were identified in the CYP2D6 gene, followed by CYP2C19, CYP3A4, and CYP3A5. Of these 22 patients, seven patients had at least one major criterion (drug interactions may lead to severe clinical effects), and eight patients with reported moderate criteria (may lead to substantial clinical effects). Additionally, seven patients had variants with both major and moderate criteria. Patients were taking an average of 10 medications per person ranging from 3-19 drugs. No patient, however, experienced significant drug toxicity during the observation interval. Conclusions: Patients with advanced cancer are at particular risk for polypharmacy and adverse drug reactions. Our data report supports pharmacogenetics testing as being feasible for oncology patients. Therefore, programs to prevent or limit the frequency and severity of drug reactions warrant further exploration as they offer the potential to improve patient safety and decrease healthcare costs.

Role of Pharmacogenetics in Adverse Drug Reactions: An Update towards Personalized Medicine.

Adverse drug reactions (ADRs) are an important and frequent cause of morbidity and mortality. ADR can be related to a variety of drugs, including anticonvulsants, anaesthetics, antibiotics, antiretroviral, anticancer, and antiarrhythmics, and can involve every organ or apparatus. The causes of ADRs are still poorly understood due to their clinical heterogeneity and complexity. In this scenario, genetic predisposition toward ADRs is an emerging issue, not only in anticancer chemotherapy, but also in many other fields of medicine, including hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anemia, porphyria, malignant hyperthermia, epidermal tissue necrosis (Lyell’s Syndrome and Stevens-Johnson Syndrome), epilepsy, thyroid diseases, diabetes, Long QT and Brugada Syndromes. The role of genetic mutations in the ADRs pathogenesis has been shown either for dose-dependent or for dose-independent reactions. In this review, we present an update of the genetic background of ADRs, with phenotypic manifestations involving blood, muscles, heart, thyroid, liver, and skin disorders. This review aims to illustrate the growing usefulness of genetics both to prevent ADRs and to optimize the safe therapeutic use of many common drugs. In this prospective, ADRs could become an untoward “stress test,” leading to new diagnosis of genetic-determined diseases. Thus, the wider use of pharmacogenetic testing in the work-up of ADRs will lead to new clinical diagnosis of previously unsuspected diseases and to improved safety and efficacy of therapies. Improving the genotype-phenotype correlation through new lab techniques and implementation of artificial intelligence in the future may lead to personalized medicine, able to predict ADR and consequently to choose the appropriate compound and dosage for each patient.