Simultaneous Use of Amiodarone Influences Warfarin Maintenance Dose but Is Not Associated with Adverse Events

Santos, Paulo Caleb Júnior Lima; Soares, Renata; Strunz, Celia Maria Cassaro; Grinberg, Max; Ferreira, João Fernando Monteiro; Cesar, Luiz Antônio Machado; Scanavacca, Maurício; Krieger, José Eduardo; Pereira, Alexandre C.

doi:10.18553/jmcp.2014.20.4.376

Cited by 18 publications

(16 citation statements)

References 32 publications

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“…In the same study, co-medication with carbamazepine warranted a massive 40% increase in the dispensed dose of warfarin because of the CYP2C9 enzyme-inducing effect of carbamazepine. In a more recent study by Santos et al [67], 111 (12.8%) of the 866 patients maintained on warfarin were concurrently taking amiodarone, and the maintenance dose of warfarin was significantly lower (by 19.6%) in these patients compared with the 755 who were not on amiodarone. The frequency of patients whose international normalized ratio (INR) was within the therapeutic range was 51.4% in the users and 60.5% in the non-users of amiodarone.…”

Section: Genotype-dependent Susceptibility To Phenoconversionmentioning

confidence: 89%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

220

217

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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Section: Genotype-dependent Susceptibility To Phenoconversionmentioning

confidence: 89%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

220

217

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“…Our results partially corroborate recent evidence on drug–drug interactions (DDIs). Santos et al [42] showed that simultaneous use of warfarin and amiodarone was not associated with adverse events in chronic OAC therapy. Also, a previous study [43] found that the combination of single antiplatelet therapy with an anticoagulant was associated with a significantly greater risk of bleeding.…”

Section: Discussionmentioning

confidence: 99%

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

et al. 2016

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Vitamin K antagonists (VKAs) are highly effective but have a narrow therapeutic index and require routine monitoring of the INR. The primary aim of pharmacogenetics (PGx) is to optimize patient care, achieving drug treatments that are personalized according to the genetic profile of each patient. The best-characterized genes involved in VKA PGx involve pharmacokinetics (VKORC1) and pharmacodynamics (CYP2C9) of VKA metabolism. The role of these genes in clinical outcomes (bleeding and thrombosis) during oral anticoagulant (OAC) therapy is controversial. The aim of the present study was to evaluate any potential association between genotype VKORC1 and CYP2C9 and adverse events (hemorrhagic and/or thrombotic), during initiation and long-term VKA treatment, in Caucasian patients. Furthermore, we aimed to determine if the concomitant prescription of other selected drugs affected the association between genotype and adverse events.We performed a retrospective, matched case-control study to determine associations between multiple gene variants, drug intake, and any major adverse effects in anticoagulated patients, monitored in 2 Italian anticoagulation clinics.Our results show that anticoagulated patients have a high risk of adverse events if they are carriers of 1 or more genetic polymorphisms in the VKORC1 (rs9923231) and CYP2C9 (rs1799853 and rs1057910) genes.Information on CYP2C9 and VKORC1 variants may be useful to identify individualized oral anticoagulant treatment for each patient, improve management and quality of VKA anticoagulation control, and monitor drug surveillance in pharmacovigilance programs.

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“…A drug-drug interaction of amiodarone with VKAs is also well-known. VKA maintenance dose is lower in patients simultaneously using amiodarone compared with patients without amiodarone, and patients taking amiodarone have higher INR/current dose ratios compared with patients not using amiodarone [18]. It is uncertain, however, to which degree amiodarone affects the anticoagulant effects of rivaroxaban [19].…”

Section: Discussionmentioning

confidence: 99%