scholarly journals Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients

2018 ◽  
Vol 9 ◽  
Author(s):  
Letícia C. Tavares ◽  
Leiliane R. Marcatto ◽  
Renata A. G. Soares ◽  
Jose E. Krieger ◽  
Alexandre C. Pereira ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Abcb1 Polymorphism

Predicting the Dose of Warfarin for Therapeutic Anticoagulation

1982 ◽  
Vol 47 (03) ◽  
pp. 230-231 ◽  
Author(s):  
N K Sharma ◽  
P A Routledge ◽  
M D Rawlins ◽  
D M Davies
Keyword(s):  
Therapeutic Range ◽  
Significant Relationship ◽  
Maintenance Dose ◽  
Warfarin Dose ◽  
Loading Dose ◽  
Intravenous Injections ◽  
Therapeutic Anticoagulation ◽  
Close Relationship ◽  
The Relationship ◽  
Anticoagulant Response

SummaryThe validity of a previously described technique for predicting warfarin requirements based on the anticoagulant response to a fixed loading dose was assessed prospectively in 57 patients. There was a close relationship between the predicted and initially observed daily warfarin dose required to maintain the patient within the therapeutic range for anticoagulation. The significant relationship between predicted and observed maintenance dose persisted at 4 and 12 weeks although it decreased with increasing time.The relationship between observed and predicted maintenance requirement of warfarin was not affected by the concomitant use of intermittent intravenous injections of heparin when 9 hr was allowed to elapse between the previous dose of heparin and the thrombotest estimation on which the prediction was based.It is concluded that the method is valuable in predicting an individual’s warfarin requirement, although it does not obviate the need for regular monitoring of anticoagulant control.

The Negative Impact of Biological Variation in the Effect and Clearance of Warfarin on Methods for Prediction of Dose Requirements

1986 ◽  
Vol 56 (03) ◽  
pp. 371-375 ◽  
Author(s):  
Peretz Weiss ◽  
Hillel Halkin ◽  
Shlomo Almog
Keyword(s):  
Individual Variation ◽  
Negative Impact ◽  
Warfarin Dose ◽  
Empirical Therapy ◽  
Maintenance Phase ◽  
Individual Variability ◽  
Dose Prediction ◽  
Group I ◽  
Over Time ◽  
Variance Explained

SummaryWithin-individual variation over time in the clearance (Cl) and effect (PT%) of warfarin, was measured in 25 inpatients (group I) studied after standard single or individualized split loading doses and 1-3 times (n = 16) 8-16 weeks later during maintenance. Mean Cl (2.5 α 0.9 ml/min) was similar in both phases but significant changes occurred in 6/16 patients, exceeding those expected from within-individual variation alone (defined by its 95% tolerance limits -24% to +62%). Initial PT% (21 α 5) was unaffected by dosing schedule, total or free plasma warfarin, varying between patients by only 18-24%. Mean initial and maintenance dose-PT% ratios (8.2 mg/d: 21% and 4.1 mg/d: 40%) were similar but significant changes in sensitivity to warfarin occurred in 4/16 patients. In group I and 64 other outpatients on maintenance therapy, between-individual variability was 36-52% for Cl and 49-56% for effect. PT% correlated best (r = 0.56) with free and total plasma warfarin but poorly with dose (r = 0.29), with only 30% of PT% variance explained at best, due to high between patient variability.Warfarin dose prediction whether based on extrapolation from initial effects to the maintenance phase, or on iterative methods not allowing for between- or within-patient variation in warfarin clearance or effect which may occur independently over time, have not improved on empirical therapy. This, due to the elements of biological variability as well as the intricacy of the warfarin - prothrombin complex interaction not captured by any kinetic-dynamic model used for prediction to date.

COMPUTER PREDICTION OF ANTICOAGULATION STATUS AND WARFARIN DOSE FOLLOWING CARDIAC SURGERY

1987 ◽  
Author(s):  
M J Crow ◽  
A B Latif ◽  
A I Critchley ◽  
C Stainton ◽  
P Nealon ◽  
...  
Keyword(s):  
Therapeutic Range ◽  
Maintenance Dose ◽  
Prosthetic Heart Valve ◽  
Warfarin Dose ◽  
Study Data ◽  
Computer Prediction ◽  
Prothrombin Activity ◽  
Upper Limit ◽  
Post Operative Period ◽  
Post Operation

Fluctuations are freguently seen in the anticoagulant status of patients in the immediate post operative period following prosthetic heart valve replacement. These patients are at high risk of haemorrhage or thromboembolism. We have used a pharmokinetic model of warfarin metabolism to develop a computer programme to predict the maintenance dose of warfarin from early prothrombin activity determinations. This will enable controlled anticoagulation to be achieved. The expression for warfarin kinetics employs 4 constants determined by the residual sum of the sguares, which are used immediately to redefine dosage predictions. In a pilot study data obtained from 16 patients post operation 3, 5 and 7 days after commencing treatment, has been used to predict the reguired maintenance dose at 21 days. These predicted doses were then compared with the maintenance dose achieved by clinical practice. The programme was told to optimise its dose to achieve a PT ratio of 3 whereas clinically the ratio was allowed to vary in the therapeutic range of 2 to 4. Predicted doses at 21 days are shown.in the table:Correlation between predicted and clinical maintenance doses after 3 and 5 days treatment was poor but had improved significantly by 7 days, despite similar levels of prothrombin activity. Predicted prothrombin activity never exceeded the upper limit of the therapeutic range, and the predicted dose can be uprated on addition of further data within 2 minutes.After 7 days computer predicted warfarin dose has produced a good correlation with the clinical maintenance dose (the doses of only 3 patients varying by more than 1 mg/day). The significant fluctuations seen in the prothrombin ratio during clinical dosage were not observed with computer dosing and we now feel it is safe to use this programme to anticoagulate patients post operatively.

scholarly journals Variation in VKORC1 Is Associated with Vascular Dementia

2021 ◽  
Vol 80 (3) ◽  
pp. 1329-1337
Author(s):  
Jure Mur ◽  
Daniel L. McCartney ◽  
Daniel I. Chasman ◽  
Peter M. Visscher ◽  
Graciela Muniz-Terrera ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vascular Dementia ◽  
Genetic Variant ◽  
Warfarin Dose ◽  
Uk Biobank ◽  
Parental History ◽  
Genome Wide ◽  
History Of ◽  
First Time ◽  
The Relationship

Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10–7), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10–6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = –0.29, p < 2×10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.

Pharmacogenetic algorithm for predicting daily dose of warfarin in Caucasian patients of Czech origin

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Aleš Tomek ◽  
Tereza Růžičková ◽  
Vojtěch Kaplan ◽  
Zuzana Lacinová ◽  
Simona Kumstýřová ◽  
...  
Keyword(s):  
Validation Cohort ◽  
Warfarin Dose ◽  
Therapeutic Index ◽  
Coefficient Of Determination ◽  
Dose Prediction ◽  
Pharmacogenetic Algorithm ◽  
Daily Dose ◽  
Caucasian Patients ◽  
Variant Alleles ◽  
Initiation Of Therapy

Abstract Objectives Warfarin use is limited by a low therapeutic index and significant interindividual variability of the daily dose. The most important factor predicting daily warfarin dose is individual genotype, polymorphisms of genes CYP2C9 (warfarin metabolism) and VKORC1 (sensitivity for warfarin). Algorithms using clinical and genetic variables could predict the daily dose before the initiation of therapy. The aim of this study was to develop and validate an algorithm for the prediction of warfarin daily dose in Czech patients. Methods Detailed clinical data of patients with known and stable warfarin daily dose were collected. All patients were genotyped for polymorphisms in genes CYP2C9 and VKORC1. Results Included patients were divided into derivation (n=175) and validation (n=223) cohorts. The final algorithm includes the following variables: Age, height, weight, treatment with amiodarone and presence of variant alleles of genes CYP2C9 and VKORC1. The adjusted coefficient of determination is 72.4% in the derivation and 62.3% in the validation cohort (p<0.001). Conclusions Our validated algorithm for warfarin daily dose prediction in our Czech cohort had higher precision than other currently published algorithms. Pharmacogenetics of warfarin has the potential in the clinical practice in specialized centers.

scholarly journals Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals

2021 ◽  
Vol 11 (2) ◽  
pp. 94
Author(s):  
Masaki Kumondai ◽  
Akio Ito ◽  
Evelyn Marie Gutiérrez Rico ◽  
Eiji Hishinuma ◽  
Akiko Ueda ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Three Dimensional ◽  
Warfarin Dose ◽  
Catalytic Efficiency ◽  
Therapeutic Window ◽  
Wild Type ◽  
Drug Metabolizing Enzyme ◽  
Novel Variants ◽  
Metabolizing Enzyme ◽  
Almost All

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.

scholarly journals Phenotyping of CYP 4501A2 Activity by Total Overnight Salivary Caffeine Assessment (TOSCA) in Patients on Warfarin Treatment: A Cross-Sectional Study

2017 ◽  
Vol 24 (6) ◽  
pp. 928-935 ◽  
Author(s):  
Giovanni Tarantino ◽  
Domenico Capone ◽  
Paola Contaldi ◽  
Adriana Gianno ◽  
Mosca Teresa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Drug Concentration ◽  
Ethical Issues ◽  
Single Point ◽  
Warfarin Dose ◽  
Individual Variability ◽  
Bleeding Complications ◽  
Close Monitoring ◽  
Cross Sectional ◽  
Warfarin Sodium

Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450. High CYP 450 activity may lead to low drug concentration and requires high warfarin doses to reach efficacy; conversely, low CYP 450 activity is responsible for high drug concentration and needs for low doses to avoid potential toxicity risks. The major isoforms of CYP involved in the metabolism of warfarin sodium are CYP1A2 (for the R-warfarin) and CYP2C9 (for the S-warfarin). The probes for testing CYP1A2 are phenacetin and caffeine while for CYP2C9 tolbutamide. Although S-warfarin has major activity, it was decided to exclude its phenotyping for ethical issues, being mandatory to use a drug (tolbutamide). Instead, it was chosen to test the 1A2 isoform, as the activity of the latter isoform could be investigated by using caffeine contained in the caffeinated beverages. Specifically, a single-point concentration of salivary caffeine (total overnight salivary caffeine assessment [TOSCA]) after an overnight period of the caffeinated beverages abstinence was utilized. In the present study, 75 nonsmoker patients regularly receiving warfarin sodium were enrolled. The results have showed a significant association of the warfarin dose with TOSCA values (coefficient = –0.15, standard error = 0.04, 95% confidence interval = –0.24 to –0.06, t = –3.23, P = .002). In conclusion, the phenotyping of CYP1A2 by TOSCA could be useful, if further proven, to help manage patients on warfarin in order to lessen severe adverse events.

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