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1.  Ability of VKORC1 and CYP2C9 to Predict Therapeutic Warfarin Dose During the Initial Weeks of Therapy 
BACKGROUND
CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once International Normalized Ratio (INR) values are available because INR response reflects warfarin sensitivity.
METHODS
We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses, and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs.
RESULTS
A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R2). The R2 increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R2 of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21.
CONCLUSION
Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.
doi:10.1111/j.1538-7836.2009.03677.x
PMCID: PMC3718044  PMID: 19874474
2.  Genetics InFormatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT): Rationale and Study Design 
The pharmacogenomics journal  2011;12(5):417-424.
The risk of venous thromboembolism (VTE) is higher after total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The Genetics-InFormatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT) is a 2×2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) Does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) Is a lower target International Normalized Ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR ≥ 4, and death.
doi:10.1038/tpj.2011.18
PMCID: PMC3175019  PMID: 21606949
pharmacogenetics; warfarin; randomized controlled trial; dosing algorithm
5.  Pharmacogenetic Warfarin Dose Refinements Remain Significantly Influenced by Genetic Factors after One Week of Therapy 
Thrombosis and Haemostasis  2011;107(2):232-240.
Summary
Introduction
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once INR response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation.
Materials and Methods
An international sample of 2,022 patients at 13 medical centers on 3 continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index.
Results
Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (P<0.05 vs. clinical algorithm), MAE= 4.7 mg/week.
Conclusions
A pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
doi:10.1160/TH11-06-0388
PMCID: PMC3292349  PMID: 22186998
warfarin; VKORC1; CYP2C9; pharmacogenetic
6.  Gamma-glutamyl carboxylase and its influence on warfarin dose 
Thrombosis and haemostasis  2010;104(4):750-754.
Background
Via generation of vitamin K-dependent proteins, gamma-glutamyl carboxylase (GGCX) plays a critical role in the vitamin K cycle. Single nucleotide polymorphisms (SNPs) in GGCX, therefore, may affect dosing of the vitamin K antagonist, warfarin.
Methods
In a multi-centered, cross-sectional study of 985 patients prescribed warfarin therapy, we genotyped for two GGCX SNPs (rs11676382 and rs12714145) and quantified their relationship to therapeutic dose.
Results
GGCX rs11676382 was a significant (p=0.03) predictor of residual dosing error and was associated with a 6.1% reduction in warfarin dose (95% CI: 0.6%-11.4%) per G allele. The prevalence was 14.1% in our predominantly (78%) Caucasian cohort, but the overall contribution to dosing accuracy was modest (partial R2 = 0.2%). GGCX rs12714145 was not a significant predictor of therapeutic dose (p = 0.26).
Conclusions
GGCX rs11676382 is a statistically significant predictor of warfarin dose, but the clinical relevance is modest. Given the potentially low marginal cost of adding this SNP to existing genotyping platforms, we have modified our non-profit website (www.WarfarinDosing.org) to accommodate knowledge of this variant.
doi:10.1160/TH09-11-0763
PMCID: PMC2949522  PMID: 20694283
gamma-glutamyl carboxylase; warfarin; pharmacogenetics; algorithm
7.  Interactive Modeling for Ongoing Utility of Pharmacogenetic Diagnostic Testing: Application for Warfarin Therapy 
Clinical chemistry  2009;55(10):1861-1868.
BACKGROUND
The application of pharmacogenetic results requires demonstrable correlations between a test result and an indicated specific course of action. We developed a computational decision-support tool that combines patient-specific genotype and phenotype information to provide strategic dosage guidance. This tool, through estimating quantitative and temporal parameters associated with the metabolism- and concentration-dependent response to warfarin, provides the necessary patient-specific context for interpreting international normalized ratio (INR) measurements.
METHODS
We analyzed clinical information, plasma S-warfarin concentration, and CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genotypes for 137 patients with stable INRs. Plasma S-warfarin concentrations were evaluated by VKORC1 genotype (−1639G>A). The steady-state plasma S-warfarin concentration was calculated with CYP2C9 genotype–based clearance rates and compared with actual measurements.
RESULTS
The plasma S-warfarin concentration required to yield the target INR response is significantly (P < 0.05) associated with VKORC1 −1639G>A genotype (GG, 0.68 mg/L; AG, 0.48 mg/L; AA, 0.27 mg/L). Modeling of the plasma S-warfarin concentration according to CYP2C9 genotype predicted 58% of the variation in measured S-warfarin concentration: Measured [S-warfarin] = 0.67(Estimated [S-warfarin]) + 0.16 mg/L.
CONCLUSIONS
The target interval of plasma S-warfarin concentration required to yield a therapeutic INR can be predicted from the VKORC1 genotype (pharmacodynamics), and the progressive changes in S-warfarin concentration after repeated daily dosing can be predicted from the CYP2C9 genotype (pharmacokinetics). Combining the application of multivariate equations for estimating the maintenance dose with genotype-guided pharmacokinetics/pharmacodynamics modeling provides a powerful tool for maximizing the value of CYP2C9 and VKORC1 test results for ongoing application to patient care.
doi:10.1373/clinchem.2009.125898
PMCID: PMC3131846  PMID: 19679631
8.  Laboratory and Clinical Outcomes of Pharmacogenetic vs. Clinical Protocols for Warfarin Initiation in Orthopedic Patients 
Background
Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common.
Methods
In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy.
Results
The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, perioperative blood loss, liver disease, INR values, and dose history to predict the therapeutic dose. The R2 was 82% in a derivation cohort (N = 86), and 70% when used prospectively (N = 146). The R2 of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (N = 178), and 48% in a prospective validation cohort (N = 146). In one month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7%–11.7%) in the pharmacogenetic cohort. The risk of laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.29–0.97).
Conclusions
Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, www.WarfarinDosing.org.
doi:10.1111/j.1538-7836.2008.03095.x
PMCID: PMC2920450  PMID: 18662264
Warfarin; Pharmacogenetics; Dosing Algorithm; Anticoagulants; Orthopedic Surgery

Results 1-8 (8)