Comparing outcomes and costs among warfarin-sensitive patients versus warfarin-insensitive patients using The Right Drug, Right Dose, Right Time: Using genomic data to individualize treatment (RIGHT) 10K warfarin cohort.

Oral anticoagulant (OAC) therapy has been the main treatment approach for stroke prevention for decades. Warfarin is the most widely prescribed OAC in the United States, but is difficult to manage due to variability in dose requirements across individuals. Pharmacogenomics may mitigate risk concerns related to warfarin use by fostering the opportunity to facilitate individualized medicine approaches to warfarin treatment (e.g., genome-guided dosing). While various economic evaluations exist examining the cost-effectiveness of pharmacogenomics testing for warfarin, few observational studies exist to support these studies, with even fewer using genotype as the main exposure of interest. We examined a cohort of individuals initiating warfarin therapy between 2004 and 2017 and examined bleeding and cost outcomes for the year following initiation using Mayo Clinic's billing and administrative data, as well the Mayo Clinic Rochester Cost Data Warehouse. Analyses included descriptive summaries, comparison of characteristics across exposure groups, reporting of crude outcomes, and multivariate analyses. We included N = 1,143 patients for analyses. Just over a third of our study population (34.9%) carried a warfarin-sensitive phenotype. Sensitive individuals differed in their baseline characteristics by being of older age and having a higher number of comorbid conditions; myocardial infarction, diabetes, and cancer in particular. The occurrence of bleeding events was not significantly different across exposure groups. No significant differences across exposure groups existed in either the likelihood of incurring all-cause healthcare costs or in the magnitude of those costs. Warfarin-sensitive individuals were no more likely to utilize cardiovascular-related healthcare services; however, they had lower total and inpatient cardiovascular-related costs compared to warfarin-insensitive patients. No significant differences existed in any other categories of costs. We found limited evidence that warfarin-sensitive individuals have different healthcare spending than warfarin-insensitive individuals. Additional real-world studies are needed to support the traditional economic evaluations currently existing in the literature.

Benefits of pharmacogenomics in drug development-earlier launch of drugs and less adverse events.

Currently, pharmaceutical companies are reluctant to introduce pharmacogenomics (PGx) in their practice, since cost-benefit of PGx is obscure and methodology to use PGx in drug development has not been fully established yet. The purpose of this study is to investigate advantages obtained by introducing PGx in clinical trials. Particularly, taking Warfarin as an example, we investigate benefits of Enrichment effect that raises response rate of the drug by PGx. When response rate is raised by only 5%, cost of a clinical trial can be reduced to about 40% of a conventional clinical trial. Furthermore, since period necessary for a trial also can be reduced, development period can be shortened by about 750 days. In summary, PGx enables earlier launch of a drug with less cost, representing benefit to pharmaceutical companies, patients and public as a whole.

Will there be a role for genotyping in warfarin therapy?

PURPOSE OF REVIEW: In North America warfarin is the current standard for oral anticoagulation therapy in the treatment and/or prophylaxis of different thrombotic conditions. In daily clinical practice a significant proportion of patients on long-term warfarin therapy fail to stabilize within their target therapeutic range leading to a resultant increased risk of thromboembolism or bleeding. Various authors and agencies advocate the role of genetic testing to guide warfarin dosing. RECENT FINDINGS: Evidence regarding the clinical efficacy and cost-effectiveness of genotype-based warfarin dosing has been conflicting, although some recent studies have suggested a potential benefit in certain subgroups. SUMMARY: More evidence is needed before the wide adoption of genotype-based warfarin dosing. Future studies should be designed to address outcomes such as major bleeding or recurrent thrombosis, and allow economic evaluations.

Assessment of chimeric mice with humanized liver as a tool for predicting circulating human metabolites.

The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.

Should we be applying warfarin pharmacogenetics to clinical practice? No, not now.

The U.S. Food and Drug Administration modified warfarin labeling in 2007 to suggest, but not mandate, pharmacogenetic testing. Genetic analysis is now commercially available. However, results predict only one third of all dosing variation, the value of testing in reducing bleeding and thrombosis rates remains unproved, and cost-effectiveness is not established. Careful consideration of clinical factors that influence dosing, conscientious prothrombin time monitoring, and sage dosage adjustment remain paramount in warfarin management. Further study is required before routine warfarin pharmacogenetic testing can be recommended.

Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics.

Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. We determined the frequencies of alleles, single carriers, and double carriers of single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes in a Puerto Rican cohort and gauged the impact of these polymorphisms on warfarin dosage using a published algorithm. A total of 92 DNA samples were genotyped using Luminex x-MAP technology. The polymorphism frequencies were 6.52%, 5.43% and 28.8% for CYP2C9 *2, *3 and VKORC1-1639 C>A polymorphisms, respectively. The prevalence of combinatorial genotypes was 16% for carriers of both the CYP2C9 and VKORC1 polymorphisms, 9% for carriers of CYP2C9 polymorphisms, 35% for carriers of the VKORC1 polymorphism, and the remaining 40% were non-carriers for either gene. Based on a published warfarin dosing algorithm, single, double and triple carriers of functionally deficient polymorphisms predict reductions of 1.0-1.6, 2.0-2.9, and 2.9-3.7 mg/day, respectively, in warfarin dose. Overall, 60% of the population carried at least a single polymorphism predicting deficient warfarin metabolism or responsiveness and 13% were double carriers with polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin among patients with gene polymorphisms, potentially reducing the risk of stroke or bleeding.

Individual genomes instead of race for personalized medicine.

The cost of sequencing and genotyping is aggressively decreasing, enabling pervasive personalized genomic screening for drug reactions. Drug-metabolizing genes have been characterized sufficiently to enable practitioners to go beyond simplistic ethnic characterization and into the precisely targeted world of personal genomics. We examine six drug-metabolizing genes in J. Craig Venter and James Watson, two Caucasian men whose genomes were recently sequenced. Their genetic differences underscore the importance of personalized genomics over a race-based approach to medicine. To attain truly personalized medicine, the scientific community must aim to elucidate the genetic and environmental factors that contribute to drug reactions and not be satisfied with a simple race-based approach.

Clinical factors influencing the sensitivity to warfarin when restarted after surgery.

BACKGROUND AND OBJECTIVE: Resumption of oral anticoagulation after surgery may result in a different maintenance dose of warfarin than before the procedure. Knowledge of the clinical determinants of postoperative response could help avoid excessive anticoagulation in sensitive patients or avoid extended delays in achieving a therapeutic level in resistant patients. DESIGN: Retrospective review. SUBJECTS: Two hundred warfarin-treated patients who were managed by our clinic for surgery. OUTCOME: Two independent adjudicators classified the postoperative response to warfarin as Resistant, Normal or Sensitive, based on previous maintenance dose, international normalized ratio (INR) on the day of resumption, number of days until INR of >1.9 and doses of warfarin given. A third adjudicator resolved disagreements. Clinical data were extracted from the patient records and correlated with the response. RESULTS: Interobserver agreement for classification of postoperative response was moderate (weighted kappa 0.46) with 37 (18.5%) considered resistant, 135 (67.5%) normal, 27 (13.5%) sensitive and one patient was not classifiable. The main type of surgery was cardiac. In univariable analysis only addition of amiodarone after surgery was associated with a sensitive response (P = 0.04). After adjustment for all other factors with an ordered categorical response, amiodarone remained as the sole independent risk factor (P = 0.02) for a sensitive response, odds ratio 0.41 (95% confidence interval 0.19-0.89) for Normal instead of Sensitive or for Resistant instead of Normal. CONCLUSION: Altered sensitivity to warfarin occurs in about one-third of patients after surgery and can be predicted by the introduction of concomitant amiodarone therapy but not by patient factors or the nature of the procedure. Changes in concomitant medications after surgery should alert doctors of the potential for increased sensitivity to warfarin.

Pharmaceutical-grade albumin: impaired drug-binding capacity in vitro.

BACKGROUND: Albumin is the most abundant protein in blood plasma, and due to its ligand binding properties, serves as a circulating depot for endogenous and exogenous (e.g. drugs) compounds. Hence, the unbound drug is the pharmacologically active drug. Commercial human albumin preparations are frequently used during surgery and in critically ill patients. Recent studies have indicated that the use of pharmaceutical-grade albumin is controversial in critically ill patients. In this in vitro study we investigated the drug binding properties of pharmaceutical-grade albumins (Baxter/Immuno, Octapharma, and Pharmacia & Upjohn), native human serum, and commercially available human serum albumin from Sigma Chemical Company. METHODS: The binding properties of the various albumin solutions were tested in vitro by means of ultrafiltration. Naproxen, warfarin, and digitoxin were used as ligands. HPLC was used to quantitate the total and free drug concentrations. The data were fitted to a model of two classes of binding sites for naproxen and warfarin and one class for digitoxin, using Microsoft Excel and Graphpad Prism. RESULTS: The drugs were highly bound to albumin (95-99.5%). The highest affinity (lowest K1) was found with naproxen. Pharmaceutical-grade albumin solutions displayed significantly lower drug-binding capacity compared to native human serum and Sigma albumin. Thus, the free fraction was considerably higher, approximately 40 times for naproxen and 5 and 2 times for warfarin and digitoxin, respectively. The stabilizers caprylic acid and N-acetyl-DL-tryptophan used in the manufacturing procedure seem to be of importance. Adding the stabilizers to human serum and Sigma albumin reduced the binding affinity whereas charcoal treatment of the pharmaceutical-grade albumin from Octapharma almost restored the specific binding capacity. CONCLUSION: This in vitro study demonstrates that the specific binding for warfarin and digitoxin is significantly reduced and for naproxen no longer detectable in pharmaceutical-grade albumin. It further shows that the addition of stabilizers may be of major importance for this effect.

Polymorphism induced sensitivity to warfarin: a review of the literature.

Warfarin is a widely prescribed anticoagulant used for prophylaxis and treatment of venous and arterial thrombosis. Although warfarin is considered very efficacious, it has substantial risks associated with its use, specifically the risk of hemorrhage. Genetic variants associated with the metabolism of (S)-warfarin by cytochrome P450 2C9 may have specific implications on untoward effects. Twelve CYP2C9 allelic variants have been identified, of which CYP2C9*3 and CYP2C9*2 are the most clinically important. Studies have demonstrated that initial dosing of warfarin with CYP2C9*3 with a five-milligram dose caused an increase in the international normalized ratio and significant risk of bleeding. Studies conducted with CYP2C9*2, on the other hand are conflicting. Some data suggest that the CYP2C9*2 variant is associated with an increased propensity for bleeding whereas other studies do not demonstrate a substantial risk of adverse events. Researchers suggest that detection of genetic variants in susceptible individuals will not only decrease the risks associated with warfarin therapy but also decrease costs of adverse events.