Several-fold increase in risk of overanticoagulation by CYP2C9 mutations

Division of Clinical Pharmacology, Department of Laboratory Medicine, Institute of Environmental Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 12/2005; 78(5):540-50. DOI: 10.1016/j.clpt.2005.08.006
Source: PubMed


Our objective was to prospectively study the impact of CYP2C9 polymorphism (*2 and *3) on the risk of overanticoagulation during the induction phase of warfarin therapy.
Blood samples for genotyping were collected from 219 patients requiring warfarin therapy, and clinical data were prospectively collected during the first 3 weeks of medication. Patients were divided into 3 groups according to CYP2C9 genotype, as follows: *1 (homozygous), *2 (*1/*2 and *2/*2), and *3 (any genotype containing the *3 allele).
During the first week of treatment, the relative risk of achieving at least 1 international normalized ratio (INR) value above the therapeutic interval (2-3) was 2.8 (95% confidence interval, 1.2-6.7) and 6.1 (2.7-13.6) in the *2 and *3 groups, respectively (with *1 used as control). During the second week, the corresponding values were 2.1 (1.2-3.7) and 3.5 (2.1-5.8), respectively. By the third week, the genetic impact was no longer evident, presumably as a result of successful dose individualization. Increased INR levels (compared with the *1 group) were already demonstrated in the *2 group on the fourth treatment day.
The CYP2C9*2 and *3 single-nucleotide polymorphisms significantly increase the risk of overanticoagulation during the first 2 weeks of warfarin treatment, with increased INR levels evident after only 4 days' treatment in *2 carriers. Our prospective data are consistent with results from previous retrospective studies and indicate that CYP2C9 genotyping may be a means of improving safety during warfarin induction.

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    • "Once the dosage is stabilised, it appears that CYP2C9 polymorphisms influence the effect of oral anticoagulation to a lesser extent [123, 124]. In some studies, it has also been reported that the occurrence of supratherapeutic INRs was higher in patient carriers of these polymorphisms [122, 125]. The CYP2C9*2 allele seems to have less influence on the dose of acenocoumarol or phenprocoumon compared to warfarin [121, 122, 126, 127]. "
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    ABSTRACT: Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homozygous and heterozygous carriers of CYP2C9 variant alleles require lower doses of phenytoin to reach therapeutic plasma concentrations, and are at increased risk of toxicity. New diagnostic techniques made safer and easier should allow quicker diagnosis of metabolic variations. Genotyping and phenotyping may therefore be considered where dosing guidelines according to CYP genotype have been published, and help identify the right molecule for the right patient.
    Molecular Diagnosis & Therapy 04/2013; 17(3). DOI:10.1007/s40291-013-0028-5 · 2.89 Impact Factor
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    • "A tendency to an association between variant alleles and INR46, but no association with bleeding Lindh et al. (2005) 38 Swedish 219 CYP2C9*2 and *3 associated with low dose "
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    ABSTRACT: Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P(450) 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.
    The Pharmacogenomics Journal 05/2007; 7(2):99-111. DOI:10.1038/sj.tpj.6500417 · 4.23 Impact Factor
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    ABSTRACT: BackgroundGenotype-guided initial warfarin dosing may reduce over-anticoagulation and serious bleeding compared to a one-dose-fits-all dosing method. ObjectiveThe objective of this review was to investigate the safety and efficacy of genotype-guided dosing of warfarin in reducing the occurrence of serious bleeding events and over-anticoagulation. Data SourcesThe authors searched PubMed, EMBASE and International Pharmaceutical Abstracts through January 23, 2009, without language restrictions. Selected articles were randomized trials comparing pharmacogenetic dosing of warfarin versus a “standard” dose control algorithm in adult patients taking warfarin for the first time. Review MethodsTwo reviewers independently extracted data and assessed study quality using a validated instrument. The primary outcomes were major bleeding and time spent within the therapeutic range International Normalized Ratio (INR). Secondary outcomes included minor bleeding, thrombotic events and other measures of anticoagulation quality. ResultsThree of 2,014 studies (423 patients) met the inclusion and exclusion criteria. Differences in study quality, dosing algorithms, length of follow-up and outcome measures limited meta-analysis. Summary estimates revealed no statistically significant difference in bleeding rates or time within the therapeutic range INR. The highest quality study found no significant difference in primary or secondary outcomes, although there was a trend towards more rapid achievement of a stable dose (14.1 vs. 19.6 days, p = 0.07) in the pharmocogenetic arm. ConclusionsWe did not find sufficient evidence to support the use of pharmacogenetics to guide warfarin therapy. Additional clinical trials are needed to define the optimal approach to use warfarin pharmacogenetics in clinical practice.
    Journal of General Internal Medicine 05/2009; 24(5):656-664. DOI:10.1007/s11606-009-0949-1 · 3.45 Impact Factor
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