Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic
01 Jan 2013-
TL;DR: Evidence from published literature is presented for CYP 2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants.
About: The article was published on 2013-01-01 and is currently open access. It has received 448 citations till now. The article focuses on the topics: Guideline & Dosing.
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University of Mainz1, University of Freiburg2, University of Würzburg3, Federal Institute for Drugs and Medical Devices4, RWTH Aachen University5, University of Regensburg6, University of Göttingen7, University of Tübingen8, Innsbruck Medical University9, University of Bern10, Ludwig Maximilian University of Munich11, Technische Universität München12, Max Planck Society13, University of Lausanne14
TL;DR: Following the new guidelines for therapeutic drug monitoring in psychiatry holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.
Abstract: Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.
827 citations
Cites methods from "Clinical Pharmacogenetics Implement..."
...Pharmacogenetics 2004; 14: 225–238 [515] Hicks JK, Bishop JR, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors....
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...In agreement with recommendations of the German Commission Genetic Testing (GeKO) and the Clinical Pharmacogenetics Implementation Consortium [515, 517, 1229] as well as regulatory administrations such as the FDA and EMA the most important indications for genotyping of drug metabolizing enzymes in combination with TDM are the following: ▪ A priori genotyping when a drug is characterized by a small therapeutic index with a risk of toxicity in the case of a genetically impaired metabolism....
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...Clin Pharmacol Ther 2017; 102: 37–44 [517] Hicks JK, Swen JJ, Thorn CF et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants....
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TL;DR: The Mood Disorder CPG is the first Clinical Practice Guideline to address both depressive and bipolar disorders and provides up-to-date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus.
Abstract: Objectives: To provide guidance for the management of mood disorders, based on scientific evidence supplemented by expert clinical consensus and formulate recommendations to maximise clinical salience and utility. Methods: Articles and information sourced from search engines including PubMed and EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (MDC) (e.g., books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Information was reviewed and discussed by members of the MDC and findings were then formulated into consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous successive consultation and external review involving: expert and clinical advisors, the public, key stakeholders, professional bodies and specialist groups with interest in mood disorders. Results: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (Mood Disorders CPG) provide up-to-date guidance and advice regarding the management of mood disorders that is informed by evidence and clinical experience. The Mood Disorders CPG is intended for clinical use by psychiatrists, psychologists, physicians and others with an interest in mental health care.
643 citations
TL;DR: Current programs that use preemptive genotyping to optimize the pharmacotherapy of patients are discussed and key processes for implementation are highlighted, including clinical decision support.
Abstract: Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support.
366 citations
TL;DR: This comprehensive study summarizes allele frequencies, diplotypes, and predicted phenotype across major populations, providing a rich data resource for clinicians and researchers.
354 citations
Stanford University1, University of Toronto2, Bosch3, University of Tübingen4, University of Extremadura5, National Institutes of Health6, Academia Sinica7, China Medical University (Taiwan)8, Vanderbilt University9, Icahn School of Medicine at Mount Sinai10, Uppsala University11, Leiden University12, Geisinger Medical Center13
TL;DR: This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.
Abstract: The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
329 citations
Cites background or methods from "Clinical Pharmacogenetics Implement..."
...At the time of this writing, CPIC has published nine gene-drug guidelines [2-10], two of which have recently been updated [11, 12]....
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...The first eight CPIC guidelines and the first guideline update [2-9, 11] have already been cited numerous times in other published literature....
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References
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TL;DR: General agreement of genetic and predefined populations suggests that self-reported ancestry can facilitate assessments of epidemiological risks but does not obviate the need to use genetic information in genetic association studies.
Abstract: We studied human population structure using genotypes at 377 autosomal microsatellite loci in 1056 individuals from 52 populations. Within-population differences among individuals account for 93 to 95% of genetic variation; differences among major groups constitute only 3 to 5%. Nevertheless, without using prior information about the origins of individuals, we identified six main genetic clusters, five of which correspond to major geographic regions, and subclusters that often correspond to individual populations. General agreement of genetic and predefined populations suggests that self-reported ancestry can facilitate assessments of epidemiological risks but does not obviate the need to use genetic information in genetic association studies.
2,661 citations
TL;DR: Carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Abstract: Background Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38. Results In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to ...
2,326 citations
University of Rochester1, University of Wisconsin-Madison2, University of Pennsylvania3, Aarhus University Hospital4, Helsinki University Central Hospital5, University of Washington6, University of California, San Francisco7, University of Liverpool8, Beth Israel Medical Center9, Imperial College London10, Oregon Health & Science University11, University of Mainz12, University of California, San Diego13
TL;DR: Patients with neuropathic pain are challenging to manage and evidence‐based clinical recommendations for pharmacologic management are needed, and medications should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary.
Abstract: Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.
1,962 citations
TL;DR: Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not, particularly marked among the patients undergoing percutaneous coronary intervention.
Abstract: Background Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. Methods We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Results Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-offunction alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Conclusions Among patients with an acute myocardial infarction who were receiving clo pid ogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials. gov number, NCT00673036.)
1,623 citations
TL;DR: The Pharmacogenomics Knowledgebase is a useful source of high‐quality information supporting personalized medicine–implementation projects.
Abstract: The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene-drug associations and genotype-phenotype relationships. Curators assign levels of evidence to variant-drug associations using well-defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high-quality information supporting personalized medicine-implementation projects.
1,526 citations