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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 -
Canadian Journal of Psychiatry. Revue... Dec 2021Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to...
BACKGROUND
Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID.
METHODS
We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects).
RESULTS
A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of and polymorphisms, respectively, yielding mostly negative study findings.
CONCLUSIONS
There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.
Topics: Adolescent; Adult; Antipsychotic Agents; Autism Spectrum Disorder; Child; Humans; Intellectual Disability; Pharmacogenomic Testing; Psychotropic Drugs; Serotonin Plasma Membrane Transport Proteins
PubMed: 33222504
DOI: 10.1177/0706743720971950 -
Pharmacogenetics and Genomics Dec 2020We built a novel mock pharmacogenomics web portal to deliver pharmacogenomic information and results to patients. Utilizing a patient focus group, we then sought to...
OBJECTIVES
We built a novel mock pharmacogenomics web portal to deliver pharmacogenomic information and results to patients. Utilizing a patient focus group, we then sought to understand patient insights on desired features of an effective pharmacogenomics patient portal.
METHODS
The mock YourPGx Portal delivered four sample pharmacogenomic results (omeprazole, simvastatin, clopidogrel, and codeine). Patients from our existing institutional, prospective pharmacogenomics implementation study were recruited to pilot the mock portal and then asked to participate in a focus group discussion led by two facilitators. All patients had been previously genotyped, but none had been directly provided access to their own genotyping results and none had previously used the YourPGx portal. The focus group discussion explored nine domains: (1) factors influencing drug response, (2) concerns about drug effects, (3) understanding of genomics and pharmacogenomics, (4) reasons to undergo pharmacogenomic testing, (5) sources of pharmacogenomic information for patient education, (6) attributes of pharmacogenomic sources of information, (7) considerations about privacy and personal pharmacogenomic information, (8) sharing of pharmacogenomic information, and (9) features of an effective patient portal.
RESULTS
The median age of patients (n = 10) was 65.5 years old (range 38-72), 70% female, 50% Caucasian/30% Black, and 60% held a bachelor/advanced degree. When asked about resources for seeking pharmacogenomic information, patients preferred consulting their providers first, followed by self-education, then using information provided by university research organizations. A theme emerged regarding attributes of these sources, namely a desire for understandability and trust. Patients said that the effectiveness of a pharmacogenomics patient portal is improved with use of symbolisms/graphics and clear and concise content. Effective use of colors, quantifying information, consistency, and use of layperson's language were additional important facets. Patients communicated the appeal of secured phone/app-enabled access and said that they would desire linking to their electronic medical records to allow sharing of information with different members of their healthcare team.
CONCLUSIONS
Patients named providers as their primary source of pharmacogenomic information, but a pharmacogenomics patient portal that is carefully constructed to incorporate desired features may be a favorable tool to effectively deliver pharmacogenomic information and results to patients.
Topics: Adult; Aged; Female; Follow-Up Studies; Health Knowledge, Attitudes, Practice; Humans; Male; Middle Aged; Patient Acceptance of Health Care; Patient Portals; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine; Prospective Studies; Surveys and Questionnaires
PubMed: 33017129
DOI: 10.1097/FPC.0000000000000413 -
Dialogues in Clinical Neuroscience Sep 2016Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing... (Review)
Review
Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing pharmacokinetics and pharmacodynamics may contribute to some of this variability. Research studies have characterized these pharmacogenetic relationships, and some genetic markers are now available as clinical tests. These advances in pharmacogenetics research and test availability have great potential to improve clinical outcomes and quality of life in psychiatric patients. For clinicians considering using pharmacogenetics, it is important to understand the clinical implications and also the limitations of markers included in currently available tests. This review focuses on pharmacokinetic and pharmacodynamic gene variants that are currently available in commercial genetic testing panels. Associations of these variants with clinical efficacy and adverse effects, as well as other clinical implications, in antipsychotic pharmacotherapy are discussed.
Topics: ATP Binding Cassette Transporter, Subfamily B; Antipsychotic Agents; Catechol O-Methyltransferase; Cytochrome P-450 Enzyme System; Genetic Markers; Humans; Mental Disorders; Pharmacogenomic Testing; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2
PubMed: 27757066
DOI: 10.31887/DCNS.2016.18.3/jbishop -
Pharmacology Research & Perspectives Dec 2020Clopidogrel is the most common and widely used antiplatelet agent for patients with coronary artery disease following confirmation by electrocardiographic studies. The... (Review)
Review
Clopidogrel is the most common and widely used antiplatelet agent for patients with coronary artery disease following confirmation by electrocardiographic studies. The nonresponsiveness of patients to clopidogrel and the possibility of testing for clopidogrel resistance by platelet function assays (PFA) are contentious issues. Light transmission aggregometry (LTA) is considered as the gold standard test among all PFA. In this review, the most commonly used PFA used for monitoring the effect of clopidogrel, LTA, vasodilator-stimulated phosphoprotein assay phosphorylation, rotational thromboelastometry (ROTEM) delta and ROTEM platelet, thromboelastography, PFA-100, VerifyNow P2Y12 assay, Multiplate analyzer, Plateletworks assay and pharmacogenetic studies, are comparatively discussed including their principles of action, advantages, and disadvantages. VerifyNow P2Y12 assay can be accepted as the ideal point of care test out of the discussed assays. However, modified assays are required which could overcome the limitations associated with currently available assays.
Topics: Animals; Clopidogrel; Drug Monitoring; Humans; Pharmacogenetics; Pharmacogenomic Testing; Platelet Aggregation Inhibitors; Platelet Function Tests; Point-of-Care Systems; Thrombelastography
PubMed: 33200888
DOI: 10.1002/prp2.686 -
Annals of Medicine Dec 2020Statins are the first-line choice in Lipid-lowering therapy to reduce cardiovascular risk. In a continuous attempt to optimise treatment success, there is a need for... (Review)
Review
Statins are the first-line choice in Lipid-lowering therapy to reduce cardiovascular risk. In a continuous attempt to optimise treatment success, there is a need for additional research on genes and related molecular pathways that can determine the efficacy and toxicity of lipid-lowering drugs. Several variations within genes associated with lipid metabolism, including those involved in uptake, distribution and metabolism of statins have been reported. The purpose of this study was to evaluate the effect of genetic variations in the key genes responsible for statins' metabolism and their role in personalised medicine and pharmacogenetic testing (PGx) in patients treated with such drugs. Genetic assessment for specific known SNPs within the most known genes such as , and , appears likely to predict the efficacy of statin therapy and prevent their side effects but does not necessarily reduce the risk of cardiovascular events. Key Messages Hypercholesterolaemia patients show different response to statin therapy. Several variations within genes associated with statin metabolism have been investigated. Genetic assessment for specific known SNPs within the most known genes may improve the efficacy of statins treatment and prevent their side effects.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Cardiovascular Diseases; Cytochrome P-450 CYP3A; Feasibility Studies; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver-Specific Organic Anion Transporter 1; Neoplasm Proteins; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precision Medicine; Prognosis; Risk Assessment; Treatment Outcome
PubMed: 32735150
DOI: 10.1080/07853890.2020.1800074