Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy ...established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics‐based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine‐S‐methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA‐B44, HLA‐B*5701, CYP3A5, and factor V Leiden (FVL).
Clinical Pharmacology & Therapeutics (2011) 89 5, 662–673. doi:10.1038/clpt.2011.34
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Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) ...generally have decreased dose‐adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).
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The cytochrome P450 2D6 (CYP2D6) enzyme contributes to the metabolism and/or bioactivation of approximately 25% of clinically used drugs. The CYP2D6 gene locus is highly polymorphic and complex, and ...variants within this gene locus affect CYP2D6 enzymatic function resulting in a wide range of metabolic activity from little to no activity to ultrarapid metabolism. For many of the drugs metabolized by CYP2D6, the variation in metabolic activity is one of the most important factors responsible for interindividual drug response. Therefore, determining an individual's CYP2D6 phenotype, or metabolic status, will help identify individuals that may benefit from a change in drug or drug dosage. Genotype analysis has become the method of choice to predict a person's metabolic status. Numerous reference laboratories now offer CYP2D6 genotyping; however, there can be substantial differences in the number of genetic variants interrogated as well as test interpretation. Furthermore, there is no standardized process of how a CYP2D6 genotype result is translated into a phenotype assignment. This review summarizes the complexity of CYP2D6 genotyping and highlights the major challenges for phenotype classification. We call for the implementation of a universally accepted system for CYP2D6 phenotype assignment to promote consistency of test interpretation among reference laboratories and medical institutions. We propose a system that utilizes the CYP2D6 activity score system to place individuals into a continuum of activity scores - rather than using the traditional poor, intermediate, extensive and ultra-rapid metabolizer categorizations - and directly translating activity scores into clinically actionable recommendations.
Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group provide therapeutic recommendations for well‐known gene‐drug pairs. Published ...recommendations show a high rate of concordance. However, as a result of different guideline development methods used by these two consortia, differences between the published guidelines exist. The aim of this paper is to compare both initiatives and explore these differences, with the objective to achieve harmonization.
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CYP2D6
and
CYP2C19
polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and ...others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for
CYP2D6
and
CYP2C19
genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for
CYP2D6
and
CYP2C19
Genotypes and Dosing of Tricyclic Antidepressants.
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Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, ...doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants.
Clinical Pharmacology & Therapeutics (2013); 93 5, 402–408. doi:10.1038/clpt.2013.2
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Pharmacogenetics (PGx) is currently implemented in hospitals to optimize therapy with high-risk drugs. However, many drugs with dosing recommendations from the Dutch Pharmacogenetics Working Group ...and the Clinical Pharmacogenetics Implementation Consortium are used in primary care. Actionable phenotypes for the genes covered in these guidelines are common with estimates ranging from 85 to 95% of the population carrying at least one actionable phenotype. The goal of this study was to estimate the clinical impact of implementation of an upfront panel-based pharmacogenetic screening for eight genes related to drugs used in primary care for 2016.
For this study, dispensing data concerning first prescription for the period January 1-December 31, 2016, were combined with frequency data obtained in the "Implementation of Pharmacogenetics into Primary Care Project" (IP3) study to estimate the occurrence of actionable gene-drug pairs in daily practice in community pharmacies.
In 23.6% of all new prescriptions of 45 drugs (n = 856,002 new prescriptions/year), an actionable gene-drug interaction (GDI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group. More importantly, these GDIs would result in a dose adjustment or switch to another drug in 5.4% of all new prescriptions.
Consequently, with an anticipated near future where healthcare professionals will be regularly confronted with PGx test results, adjusting pharmacotherapy based on this information will become a routine task in healthcare.
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Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of ...sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of −22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.
Clinical Pharmacology & Therapeutics (2014); 96 1, 81–89. doi:10.1038/clpt.2014.47
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Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been ...initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx‐markers into routine care, because the evidence base is currently limited to specific, individual drug‐gene pairs. The Ubiquitous Pharmacogenomics (U‐PGx) Consortium, which has been funded by the European Commission's Horizon‐2020 program, aims to address this unmet need. In a prospective, block‐randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions PREPARE), pre‐emptive genotyping of a panel of clinically relevant PGx‐markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost‐effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi‐ethnic, and multihealthcare system approach.
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