Genomics in the Scientific Literature [24] - Pharmacogenomics

Genomics in the Scientific Literature
Topics in the Scientific Literature

Pharmacogenomics
1. Gene-Based Warfarin Dosing Compared With Standard of Care Practices in an Orthopedic Surgery Population: A Prospective, Parallel Cohort Study
McMillin GA, et al.
Ther Drug Monit 2010 Apr

Ther Drug Monit. 2010 Apr 8. [Epub ahead of print]

Gene-Based Warfarin Dosing Compared With Standard of Care Practices in an Orthopedic Surgery Population: A Prospective, Parallel Cohort Study.
McMillin GA, Melis R, Wilson A, Strong MB, Wanner NA, Vinik RG, Peters CL, Pendleton RC.

From the *ARUP Laboratories Institute of Clinical and Experimental Pathology; daggerUniversity of Utah Health Sciences, Department of Internal Medicine; and double daggerUniversity of Utah Health Sciences, Department of Orthopaedics, Salt Lake City, Utah.

Abstract
Warfarin remains a difficult drug to manage due to a narrow therapeutic range and wide interindividual variability in dose requirements. The relationship between warfarin sensitivity and CYP2C9 and VKORC1 variants is strong, and is the basis for several proposed dosing algorithms. Here a gene-based dosing algorithm was compared with standard of care dosing in patients receiving warfarin to prevent venous thromboembolism after joint replacement surgery. Participants (n = 229) were adults (>/=18 years) undergoing elective total hip or knee arthroplasty and receiving warfarin under the direction of a dedicated anticoagulation services team. Patients were assigned to genotype-based or standard of care dosing arms in an alternating fashion. Initial dose for patients was determined by validated algorithms from Sconce 2005 and Pendleton 2008. Management was based on INR, but dose was adjusted less aggressively for patients with CYP2C9 variants. The primary endpoint was reduction in the incidence of adverse events; additional endpoints included time to first therapeutic INR (1.8-2.9), time to first supratherapeutic INR, and percent of INR determinations that fell below, within, and above the therapeutic range. Endpoints did not achieve statistical significance, possibly due to the management of this study by a dedicated and experienced anticoagulation services team. Trends in the data suggest that patients with genetic variants progressed to a therapeutic INR faster than patients in whom genetic variants were not detected, and there were fewer adverse events in the genotype-based dosing arm. In addition, the results of this study confirm those of others demonstrating clear relationship of genotype for CYP2C9 and VKORC1 with warfarin dose requirements; as the number of variants in these genes increases, the dose requirement decreases. Of note, the gene-based algorithm utilized here significantly underpredicted the dose requirement for participants with no variants, indicating that patients with no variants should be managed with a different algorithm than patients who inherit genetic variants in CYP2C9 and/or VKORC1. In conclusion, gene-based dosing did not improve warfarin management as defined by INR dose response, using the described protocols for implementation. Findings suggest alternative strategies for dosing based on the presence or absence of genetic variants is needed.

PMID: 20386359 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20386359?dopt=Abstract


2. Psychiatric pharmacogenomic testing in clinical practice
Mrazek DA
Dialogues Clin Neurosci 2010;12(1):69-76

Dialogues Clin Neurosci. 2010;12(1):69-76.

Psychiatric pharmacogenomic testing in clinical practice.
Mrazek DA.

Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA. mrazek.david@mayo.edu

Abstract
The clinical adoption of psychiatric pharmacogenomic testing has taken place rapidly over the past 7 years. Initially, drug-metabolizing enzyme genes, such as the cytochrome P450 2D6 gene (CYP2D6), were identified. Genotyping the highly variable cytochrome P450 2D6 gene now provides clinicians with the opportunity to identify both poor metabolizers and ultrarapid metabolizers of 2D6 substrate medications. Subsequently, genes influencing the pharmacodynamic response of medications have been made available for clinical practice. Among the earliest "target genes" was the serotonin transporter gene (SLC6A4) which has variants that have been shown to influence the clinical response of patients of European ancestry when they are treated with selective serotonin reuptake inhibitors. Genotyping of some of the serotonin receptor genes is also available to guide clinical practice. The quantification of the clinical utility of pharmacogenomic testing is evolving, and ethical considerations for testing have been established. Given the increasingly clear cost-effectiveness of genotyping, it has recently been predicted that pharmacogenomic testing will routinely be ordered to guide the selection and dosing of psychotropic medications.

PMID: 20373668 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/20373668?dopt=Abstract



3. Warfarin Genotyping Reduces Hospitalization Rates Results From the MM-WES (Medco-Mayo Warfarin Effectiveness Study)
Epstein RS, et al.
J Am Coll Cardiol 2010 Apr


J Am Coll Cardiol. 2010 Apr 7. [Epub ahead of print]

Warfarin Genotyping Reduces Hospitalization Rates Results From the MM-WES (Medco-Mayo Warfarin Effectiveness Study).
Epstein RS, Moyer TP, Aubert RE, O'Kane DJ, Xia F, Verbrugge RR, Gage BF, Teagarden JR.

Department of Medical and Analytical Affairs, Medco Health Solutions, Inc., Franklin Lakes, New Jersey.

Abstract
OBJECTIVES: This study was designed to determine whether genotype testing for patients initiating warfarin treatment will reduce the incidence of hospitalizations, including those due to bleeding or thromboembolism. BACKGROUND: Genotypic variations in CYP2C9 and VKORC1 have been shown to predict warfarin dosing, but no large-scale studies have prospectively evaluated the clinical effectiveness of genotyping in naturalistic settings across the U.S. METHODS: This national, prospective, comparative effectiveness study compared the 6-month incidence of hospitalization in patients receiving warfarin genotyping (n = 896) versus a matched historical control group (n = 2,688). To evaluate for temporal changes in the outcomes of warfarin treatment, a secondary analysis compared outcomes for 2 external control groups drawn from the same 2 time periods. RESULTS: Compared with the historical control group, the genotyped cohort had 31% fewer hospitalizations overall (adjusted hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.58 to 0.82, p < 0.001) and 28% fewer hospitalizations for bleeding or thromboembolism (HR: 0.72, 95% CI: 0.53 to 0.97, p = 0.029) during the 6-month follow-up period. Findings from a per-protocol analysis were even stronger: 33% lower risk of all-cause hospitalization (HR: 0.67, 95% CI: 0.55 to 0.81, p < 0.001) and 43% lower risk of hospitalization for bleeding or thromboembolism (HR: 0.57, 95% CI: 0.39 to 0.83, p = 0.003) in patients who were genotyped. During the same period, there was no difference in outcomes between the 2 external control groups. CONCLUSIONS: Warfarin genotyping reduced the risk of hospitalization in outpatients initiating warfarin. (The Clinical and Economic Impact of Pharmacogenomic Testing of Warfarin Therapy in Typical Community Practice Settings [MHSMayoWarf1]; NCT00830570). Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PMID: 20381283 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20381283?dopt=Abstract