Interactive Modeling for Ongoing Utility of Pharmacogenetic Diagnostic Testing: Application for Warfarin Therapy

Linder, Mark W.; Homme, Marjorie Bon; Reynolds, Kristen K.; Gage, Brian F.; Eby, Charles S.; Silvestrov, Natalia; Valdes, Roland

doi:10.1373/clinchem.2009.125898

Cited by 38 publications

(32 citation statements)

References 36 publications

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“…In the 1990s candidate gene studies focused on the enzyme CYP2C9, which metabolizes the potent (S)-isomer of warfarin, found an effect of CYP2C9 genetic variants on warfarin dose [24]. It is now well-known that patients with normal metabolism, that is, no genetic variants of CYP2C9 (*1/*1), have an estimated half-life of 30-37 h, while it is prolonged to 92-203 h in patients with severely impaired metabolism (*3/*3) [25,26]. Some years later the gene VKORC1 that codes for the enzyme vitamin K epoxide reductase [27], which is the target of warfarin, was discovered [28][29][30].…”

Section: Genetic Effectsmentioning

confidence: 99%

Prediction of Warfarin Dose: Why, When and How?

Eriksson

Wadelius

2012

Pharmacogenomics

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Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

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Section: Genetic Effectsmentioning

confidence: 99%

Prediction of Warfarin Dose: Why, When and How?

Eriksson

Wadelius

2012

Pharmacogenomics

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“…PerMIT (10) is a software-based method for clinical decision support. The method employs clinical and genetic information from each patient to calculate an estimate of the theoretical maintenance dose.…”

Section: Methodsmentioning

confidence: 99%

“…These inherited characteristics have a profound effect on the clinical pharmacology of warfarin and compromise the utility of typical dosing and monitoring practices, which do not account for pharmacokinetic (PK) and pharmacodynamic (PD) differences between patients (9). These differences can be managed through prospective modeling techniques as previously described by our group (10). Ideal induction and maintenance dosage rates are dictated by the rate of drug metabolism (clearance, half-life) and target therapeutic concentration.…”

Section: Introductionmentioning

confidence: 99%

“…This approach fails to leverage the PK and PD information gained through genotyping, which can be applied for ongoing individualized therapeutic management. The Personalized Medicine Interface Tool (PerMIT) (10) extends the technique of calculating genotype-adjusted loading and maintenance dosages (3) by applying pharmacogenetic-based PK modeling to illustrate the influence of repeated dosing on plasma drug concentrations of S-warfarin. Plasma concentrations of R-warfarin are not influenced by genetic variation of CYP2C9 and thus are not considered in the model, which provides a visual representation of the relationship between INR measurements and S-warfarin concentration.…”

Section: Introductionmentioning

confidence: 99%

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Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation

Borgman¹,

Pendleton

McMillin

et al. 2012

Thromb Haemost

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Summary We performed a randomized pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 h of enrollment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient’s genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilized INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/L. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management. Clinical Trials Registration http://www.clinicaltrials.gov. Unique identifier: NCT00993200

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“…The S-7-hydroxywarfarin/S-warfarin ratio and S-warfarin/R-warfarin ratio (S/R ratio) were calculated. A volume of distribution (V d ) was obtained using the following equation: V d =warfarin dose at the day of the blood collection/(weight x S-warfarin) [21].…”

Section: Warfarin Metabolitesmentioning

confidence: 99%