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Pharmacogenomics Jul 2020COVID-19 utilizes the ACE2 pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection... (Review)
Review
COVID-19 utilizes the ACE2 pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection ranging from no symptoms to death. The source of this heterogeneity is likely multifaceted and may have a genetic component. Demographic and clinical comorbidities associated with the severity of infection suggest that possible variants known to influence the renin-angiotensin-aldosterone (RAAS) system pathway (particularly those that influence ACE2) may contribute to the heterogenous infection response. ACE2 and Ang(1-7) (the product of ACE2) seem to have a protective effect on the pulmonary and cardiac systems. Hypertension medication modulation, may alter ACE2 and Ang(1-7), particularly in variants that have been shown to influence RAAS system function, which could be clinically useful in patients with COVID-19.
Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Antihypertensive Agents; COVID-19; Coronavirus Infections; Humans; Pandemics; Peptidyl-Dipeptidase A; Pharmacogenetics; Pharmacogenomic Testing; Pneumonia, Viral; Renin-Angiotensin System
PubMed: 32501190
DOI: 10.2217/pgs-2020-0048 -
Pharmacogenomics Oct 2020Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus... (Review)
Review
Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus making identification of patient subgroups that are most likely to respond favorably crucial. In this article, pharmacogenetic research on US FDA-approved and commonly prescribed off-label medications for the treatment of AUD is comprehensively reviewed. While the field has advanced in understanding pharmacotherapies for AUD and potential genetic moderators of treatment responses, the pharmacogenetic data to guide the prescribing clinician are limited and should be interpreted with caution. Precision medicine for AUD with more beneficial treatment responses and minimal side effects remains a high priority for further research.
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32807012
DOI: 10.2217/pgs-2020-0079 -
Clinical Pharmacology and Therapeutics May 2018The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to... (Review)
Review
The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to improve the outcome of drug therapy. Two broad approaches have been taken: a point-of-care approach in which genotyping for specific variant(s) is undertaken at the time of drug prescription, and a preemptive approach in which multiple genetic variants are typed in an individual patient and the information archived for later use when a drug with a "pharmacogenetic story" is prescribed. This review addresses the current state of implementation, the rationale for these approaches, and barriers that must be overcome. Benefits to pharmacogenetic testing are only now being defined and will be discussed.
Topics: Drug Prescriptions; Genetic Variation; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 29377064
DOI: 10.1002/cpt.1035 -
Pharmacogenomics Jul 2017The diagnosis and management of functional gastrointestinal disorders (FGIDs) remain very challenging. In the era of precision medicine, it is important to individualize... (Review)
Review
The diagnosis and management of functional gastrointestinal disorders (FGIDs) remain very challenging. In the era of precision medicine, it is important to individualize the treatment of these conditions by providing targeted and effective therapies while minimizing the risk of medication side effects. By using genetic information that predicts and affects the responses to specific medications, it is anticipated that the science of pharmacogenetics in FGIDs will advance the practice of precision medicine. The pathophysiology of FGIDs is complex, involving the interaction between predisposing genetic and environmental factors. Studies have shown that genetic polymorphisms may contribute to the variable responses to specific medications among individuals with FGIDs. Genetic variations in the CYP450 system can affect the metabolism and, hence, the pharmacokinetics of drugs used to treat FGIDs. Polymorphisms in the genes controlling proteins that are involved in the direct action of medications targeting the serotonergic, cannabinoid, adrenergic and bile acid pathways can affect the pharmacologic effects of the medications. In this review, we summarize the published literature on the pharmacogenetics of FGIDs and address the potential clinical utility and future challenges in this field. Since it was the dominant topic in the majority of the articles relevant to FGIDs, our review will focus on irritable bowel syndrome.
Topics: Gastrointestinal Diseases; Humans; Pharmaceutical Preparations; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Genetic; Precision Medicine
PubMed: 28686075
DOI: 10.2217/pgs-2017-0049 -
JAMA Network Open May 2021Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs....
IMPORTANCE
Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions.
OBJECTIVES
To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research.
EXPOSURES
Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines.
MAIN OUTCOMES AND MEASURES
The number of patients for whom PGx test results warranted deviation from standard dosing regimens.
RESULTS
A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile.
CONCLUSIONS AND RELEVANCE
In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.
Topics: Adolescent; Child; Cohort Studies; Female; Genetic Testing; Humans; Male; Ontario; Pediatrics; Pharmacogenomic Testing; Pilot Projects; Point-of-Care Testing; Precision Medicine; Tertiary Healthcare
PubMed: 34037732
DOI: 10.1001/jamanetworkopen.2021.10446 -
Journal of the American Academy of... Jun 2021AACAP's recent policy statement on Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adolescents recommends that "clinicians...
AACAP's recent policy statement on Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adolescents recommends that "clinicians avoid using pharmacogenetic testing to select psychotropic medications in children and adolescents." We agree that there are limitations to the nascent evidence base for using pharmacogenetics, especially in combinatorial form (eg, test results that bin medications based on multiple genes). However, all-or-nothing recommendations fail to recognize the nuance and context of this testing and contrast with the AACAP Facts for Families on pharmacogenetic testing. Moreover, pharmacogenetic testing may inform dosing for antidepressants that are commonly used in child and adolescent psychiatry (eg, sertraline, escitalopram, citalopram, fluvoxamine) as well as the tolerability of some psychotropic medications. With this in mind, we wish to remind the AACAP community of the accumulating evidence and to highlight important principles of pharmacogenetic testing in youths. Specifically: 1) pharmacogenetic testing is not always performed by commercial companies and is not always combinatorial; 2) dosing recommendations or assessment of risk for severe hypersensitivity reactions are based on pharmacogenetics in the Food and Drug Administration (FDA)-approved product inserts for several medications commonly prescribed to children (eg, citalopram, aripiprazole, atomoxetine, carbamazepine, oxcarbazepine at www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling); 3) expert consensus guidelines for dosing or identifying hypersensitivity risk for these drugs are available from the National Institutes of Health (NIH)-supported Clinical Pharmacogenetics Implementation Consortium (CPIC, www.cpicpgx.org/), which provides transparent, regularly updated, and evidence-based evaluations of pharmacogenetic data; and 4) randomized trials are not required for clinical dose adjustments; for example, dose adjustments because of decreased hepatic function or concomitant interacting medications are based on pharmacokinetic data, similar to many pharmacokinetic gene-based recommendations from CPIC.
Topics: Adolescent; Antidepressive Agents; Child; Humans; Pharmacogenetics; Pharmacogenomic Testing; Psychopharmacology; Psychotropic Drugs
PubMed: 32860906
DOI: 10.1016/j.jaac.2020.08.006 -
MEDICC Review 2019INTRODUCTION Approximately 73% of persons with HIV who receive antiretroviral therapy in Cuba are in viral suppression. The non-response of the remaining 27% could be... (Review)
Review
INTRODUCTION Approximately 73% of persons with HIV who receive antiretroviral therapy in Cuba are in viral suppression. The non-response of the remaining 27% could be due to several factors including adverse drug reactions and HIV resistance to antiretroviral drugs, as well as social factors and idiosyncratic characteristics of each patient. Genetic information explains from 20% to 95% of a drug's effects and variations in response. Considering optimization of therapeutic efficacy in our country, genetic factors of the host should be identified. OBJECTIVE Identify polymorphisms affecting genetic variability of responses to antiretroviral drugs. EVIDENCE ACQUISITION A literature review was conducted (of original articles, published theses, clinical reports and bibliographic review studies, from 2000 to 2018, in Spanish and English listed in MEDLINE/PubMed, SciELO, LILACS, PharmGKB and Google Scholar) with the following key words: pharmacogenetics, human immunodeficiency virus, anti-retroviral agents, genetic polymorphism, genetic techniques, pharmacogenomic variants. DEVELOPMENT The review identified 77 relevant publications meeting specific quality criteria. A summary table was built with data collected on antiretroviral drugs, genes and proteins involved in polymorphic variations, their associated effects and relevant scientific references. Information was included on polymorphisms related to 12 antiretroviral drugs used in HIV therapy. Polymorphisms determine variations in proteins involved in drug transport and metabolism and in elements of immunity. Relevant pharmacogenetic biomarkers recognized by drug regulatory agencies were identified. CONCLUSIONS The study identified genetic variations (single-nucleotide polymorphisms) associated with 12 antiretroviral drugs. In most cases, no statistically significant causal association was found. Identifying polymorphic variations is a medium- and long-term objective that requires statistical support and adoption of strategies to optimize antiretroviral therapy. An approach combining plasma-level monitoring and pharmacogenetic analysis is recommended to optimize therapy for HIV patients. KEYWORDS Pharmacogenetics, HIV, anti-retroviral agents, antiretroviral therapy, genetic polymorphism, genetic techniques, pharmacogenomic variants.
Topics: Anti-HIV Agents; HIV Infections; Humans; Pharmacogenomic Testing; Precision Medicine
PubMed: 31401638
DOI: 10.37757/MR2019.V21.N2-3.11 -
Depression and Anxiety Sep 2020Novel technologies make it possible to incorporate pharmacogenetic testing into the medical management of depression. However, previous studies indicate that there may...
BACKGROUND
Novel technologies make it possible to incorporate pharmacogenetic testing into the medical management of depression. However, previous studies indicate that there may be a subset of subjects who have concerns about genetic testing and may be psychologically vulnerable. If so, pharmacogenetic testing in depressed subjects could negatively impact their mental health and undermine treatment goals.
METHODS
In this study, we developed a standardized instrument to assess motivations and attitudes around pharmacogenetic testing in a cohort of 170 depressed Veterans participating in a multi-center clinic trial.
RESULTS
Testing reveals that subjects were largely positive about the use of genetic testing to guide pharmacological treatment and help plan their future. Most subjects showed only modest concerns about the impact on family, inability to cope with the results, and fear of discrimination. The severity of depression did not predict the concern expressed about negative outcomes. However, non-Caucasian subjects were more likely on average to endorse concerns about poor coping and fear of discrimination.
CONCLUSIONS
These data indicate that while the overall risk is modest, some patients with depression may face psychosocial challenges in the context of pharmacogenetic testing. Future work should identify factors that predict distress and aim to tailor test results to different populations.
Topics: Attitude; Depression; Depressive Disorder, Treatment-Resistant; Genetic Testing; Humans; Motivation; Pharmacogenomic Testing
PubMed: 32667102
DOI: 10.1002/da.23074 -
Clinical and Translational Science Mar 2021Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit medication adherence, particularly in children and adolescents. We conducted a pragmatic study to evaluate the acceptability and feasibility and gather pilot data on the utility of PGx testing in a child and adolescent psychiatry clinic. Both physicians and families participated in the study and answered pre-survey and post-survey questionnaires to examine their attitudes toward PGx testing. Patients were randomized into implementation (N = 25) and control groups (N = 24) and underwent PGx testing at the beginning or end of the study, respectively. Clinical consult notes with genotype-guided recommendations were provided to physicians for their consideration in clinical decisions. Patient-reported symptom severity and antidepressant-related side effects were assessed at baseline and for 12 weeks. Both participating physicians and families agreed that PGx testing is a useful tool to improve medication selection. The time from sample collection to having PGx test results was ~ 10 days and 15 days to having consult notes available, which may have impaired test utility in clinical decision making. There were no differences in any clinical end point between the implementation and control arms; however, there were higher antidepressant side effect scores for CYP2D6 poor and intermediate metabolizers after the eighth week of treatment. Our findings revealed benefits and pitfalls with the use of PGx testing in the real-world clinical setting, which may inform the methodology of a larger trial focused on outcomes.
Topics: Adolescent; Ambulatory Care Facilities; Antidepressive Agents; Child; Clinical Decision-Making; Cytochrome P-450 CYP2D6; Drug-Related Side Effects and Adverse Reactions; Feasibility Studies; Female; Humans; Male; Mental Disorders; Pharmacogenomic Testing; Pharmacogenomic Variants; Pilot Projects; Precision Medicine; Prospective Studies; Severity of Illness Index; Surveys and Questionnaires
PubMed: 33166056
DOI: 10.1111/cts.12914 -
Cancer Apr 2022In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although...
BACKGROUND
In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care.
METHODS
Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5-fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab-govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high-risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies.
RESULTS
Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high-risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one-third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype.
CONCLUSIONS
These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling.
LAY SUMMARY
Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others. Pharmacogenomics is the study of how genetic variations affect an individual's response to medications. In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy. By analyzing the genetic results of >1500 patients, it was found that nearly one-third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given. Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care.
Topics: Cytochrome P-450 CYP2D6; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 35090043
DOI: 10.1002/cncr.34104