Pharmacy & Therapeutics - February 2009 - (Page 93)

MEETING HIGHLIGHTS: American Society of Human Genetics investigations to identify the impact of multiple genetic variants and environmental factors on disease risk. Methods of communicating this information to both patients and practitioners will need to improve as information is generated. The 1,000 Genomes Project represents an exciting opportunity, but it does have limitations. The most important disadvantage may be that its anonymous nature prevents the ability to make specific associations between phenotype and genotype. Dr. Collins emphasized that the project is not meant to draw these conclusions; instead, he said: [It] is a discovery project to basically build the catalogue of human genetic variation into a much more comprehensive view, reaching down into those variations that occur in the range of 1% to 5%, or even a little less. Then it will be the engine of many follow-on studies that will use that catalogue specifically to try and make connections of particular variants with particular phenotypes of their interest. volumes decreased, and episodes of bone crises were reduced. Because most type 1 Gaucher’s disease cases occur during childhood and adolescence, Dr. Andersson believes that the study should prove useful for pediatricians in tracking the progress of patients over many years of treatment. REFERENCE 1. Andersson H, Kaplan P, Kacena K, Yee J. Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type 1. Pediatrics 2008;122(6):1182–1190. Genetic Determinants of Warfarin (Coumadin) Dosage • Ralph E. McGinnis, PhD, Wellcome Trust Sanger Institute, Cambridge, U.K. A number of researchers are using genome-wide association scans (GWAS) to screen for the presence of single nucleotide polymorphisms (SNPs) that can cause differences in phenotypes. Dr. McGinnis presented results from his recently completed study that used GWAS to investigate the pharmacogenetics of warfarin (Coumadin, Bristol-Myers Squibb) dosing. Warfarin is the most widely prescribed therapy for reducing thromboembolic events. The dose needed to achieve a therapeutic International Normalized Ratio (INR) can vary from 10-fold to 20-fold among individuals, depending on various genetic and nongenetic factors. As a result, without predictive information for initial warfarin dosing, patients could have a subtherapeutic or supratherapeutic INR, putting them at a higher risk for complications, such as clotting and bleeding. SNPs associated with warfarin dosing can be used to derive more accurate estimates of patients’ responses to this agent. In earlier studies, variants in the gene encoding for vitamin K epoxide reductase complex 1 (VKORC1), the warfarin drug target, accounted for 29% of the variance in required dose. Dr. McGinnis and his team, having recently evaluated 1,523 Swedish patients from the Warfarin Genetics (WARG) cohort, concluded that significant patient benefits resulted from predicting the required dose of warfarin. The investigators noted that polymorphisms in VKORC1 were the strongest predictor of the required dose, followed by polymorphisms in the gene encoding for cytochrome P450 2C9, a warfarin-metabolizing enzyme. Combined, these two SNPs account for approximately 40% of variation in the required dose, whereas nongenetic factors (age, sex) account for approximately 15%. Dr. McGinnis and his group then searched for additional genetic predictors of the required warfarin dose. After controlling for the influence of VKORC1 and CYP 2C9, the team performed additional analyses using a GWAS to test the effect of 370,000 SNPs genotyped in more than 1,000 patients from the Warfarin Genetics cohort who were receiving warfarin. Initial results identified CYP 4F2 as one additional genetic predictor of the required dose. Although the exact mechanism by which CYP 4F2 influences warfarin dosing is unknown, polymorphisms in this SNP account for 1.5% of variations in required dosing. This finding has been replicated in a study of 588 patients (combined P value, < 0.001). In conclusion, the ability to predict warfarin dosages is Alglucerase (Ceredase) and Imiglucerase (Cerezyme) in Gaucher’s Disease • Hans Andersson, MD, Karen Gore Professor of Human Genetics, and Director, Hayward Genetics Center, Tulane University Medical School, New Orleans, La. In children with type 1 Gaucher’s disease, continuous enzyme replacement therapy with Genzyme’s alglucerase (Ceredase) or imiglucerase (Cerezyme) can help normalize most clinical parameters, according to Dr. Andersson. His eight-year longitudinal study1 “is the first of its kind to document the long-term effectiveness of enzyme replacement therapy in children with type 1 Gaucher disease,” he commented. This autosomal recessive lysosomal storage disease results from a deficiency of the lysosomal enzyme glucocerebrosidase. Patients lacking this enzyme accumulate glucocerebroside, a sugar–lipid complex, in the macrophages of the reticuloendothelial system. Characteristically, patients have signs of anemia, thrombocytopenia, organomegaly, bone disease, and delayed growth. Although three major forms of Gaucher’s disease have been identified, type 1 is recognized as the most common. Analyzing the records of 884 children sampled from the International Collaborative Gaucher Group Gaucher Registry, a voluntary observational database of patients with Gaucher’s disease, the study authors targeted the therapeutic response of seven variables—Z score for height, normalized hemoglobin level, platelet count, liver volume, spleen volume, Z score for lumbar spine bone mineral density (BMD), and bone crises—to enzymatic replacement with alglucerase, imiglucerase, or both, over eight years. A baseline assessment of the sample indicated a median height Z score of –1.4, a median normalized hemoglobin level of –0.3 g/dL, a median platelet count below 100,000/mcL, significantly enlarged liver and spleen volumes, a median BMD Z score of –0.35, and a history of bone crises in 17% of the sample population. After eight years of continuous therapy, median height and BMD approximated the median values for the normal population, anemia resolved in all patients, platelet counts improved to levels above 100,000/mcL in 95% of patients, liver and spleen Vol. 34 No. 2 • February 2009 • P&T® 93

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Pharmacy & Therapeutics - February 2009 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Pushing an Expanded Role for Pharmacists Better Asthma Management with Advanced Technology Pharmaceutical Approval Update 58th Annual Meeting, American Society of Human Genetics, 2008 American Society of Hematology, 50th Annual Meeting and Exposition 2008 San Antonio Breast Cancer Symposium Stahl’s Essential Psychopharmacology, 3rd Edition Author Guidelines

Pharmacy & Therapeutics - February 2009

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