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 WC Zamboni, S Strychor, L Maruca, S Ramalingam, BA Zamboni, H Wu, DM Friedland, RP Edwards, RG Stoller, CP Belani, and RK Ramanathan
ABSTRACT: S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients 60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1–2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.
http://www.nature.com/clpt/journal/v86/n5/full/clpt2009141a.html Collapse Publication LG Dressler and SF Terry ABSTRACT: After a 13-year battle in Congress—longer than it took to map the human genome—the Genetic Information Nondiscrimination Act (GINA) was passed into law on 21 May 2008. Before its passing, Francis Collins, then director of the National Human Genome Research Institute, testified before the 110th Congress that the success of personalized medicine hinged on the passing of the legislation. How will GINA, which takes effect in 2009, influence participation in pharmacogenomic research and clinical testing?
http://www.nature.com/clpt/journal/v86/n5/full/clpt2009146a.html
Collapse Publication Joseph Cook , Graeme Hunter, and John A. Vernon vol. 27, issue 5, pages 355-363
Abstract: This article discusses the evolving field of pharmacogenomics, which is the science of using genomic markers to predict drug response, and how it may impact the future costs, risks and returns to pharmaceutical research and development (R&D). We uncover a number of factors and issues that are likely to influence the expected returns and, hence, the incentive to invest in new pharmaceutical R&D in tandem with the development of pharmacogenomics. Specifically, we identify how pharmacogenomics may lower the cost of drug development by shortening drug development times. Thus, pharmacogenomics may lead to an increase in a drug's effective patent life, and may also increase the demand and adoption rate for new products. For these and other reasons, pharmacogenomics may one day enhance expected future returns to R&D, leading to higher levels of R&D investment and an increased pace of pharmaceutical innovation. Our conclusions must be read with much caution, however, as there is considerable uncertainty as to how the area will evolve, both clinically and economically. The time horizon necessary for the science to develop and be adopted into clinical practice is not clear. Nevertheless, we think the issues and factors outlined in this article shed light on possible future economic outcomes and changes in the industry's structure, conduct and performance. Hopefully, this will provide researchers with avenues to pursue regarding a better understanding of the economics of pharmacogenomics.
Collapse Publication Victoria M. Pratt, S. Terence Dunn and Karen E. Weck Pharmacogenomic (PGx) testing has drawn increasing attention by the promise of delivering individualized therapies and preventing adverse drug reactions (ADRs). The standard “trial and error” method for determining the appropriate choice of drug and dose of the drug contributes to nearly 3 million incorrect or ineffective drug prescriptions annually. Collapse Publication Yen-Revollo, Jane L; Auman, J Todd; McLeod, Howard L Introduction: Polymorphic alleles in the human genome have been identified as affecting numerous drug responses. Currently, genotyping of all patients before starting a drug regimen is impractical. Since many polymorphisms occur at varying rates in different racial groups, we investigated whether a patient’s race could predict presence of drug-relevant genetic variants well enough to be used as a substitute for individual genotyping.
Methods: We performed hierarchical clustering and principal components analysis (PCA) on tagSNPs from 3 pathways (irinotecan, 5-fluorouracil, insulin) across 270 individuals from 4 racial groups available from the International HapMap Project.
Results: For the drug pathways, irinotecan and 5-fluorouracil, individuals from each race were widely dispersed, although several subclusters consisted entirely of individuals from a single racial group. PCA confirmed race was not a major contributor to the SNP data variance. Interestingly, individuals tended to cluster more by race across the endogenous insulin signaling pathway SNPs.
Conclusions: Most genetic variation was determined by individual variation, not racial grouping, indicating race is not adequate as a surrogate to individualized therapy. Collapse Publication Kevin Chen Howard McLeod, PharmD, is the Director of the University of North Carolina at Chapel Hill Institute for Pharmacogenomics and Individualized Therapy (IPIT) and Fred Eshelman Distinguished Professor at the UNC-Chapel Hill School of Pharmacy. Dr. McLeod is also a member of the Food and Drug Administration (FDA)’s Clinical Pharmacology subcommittee and serves as the Vice Chair of the National Institutes of Health Cancer and Leukemia Pharmacology and Experimental Therapeutics committee. His pioneering efforts in the field of pharmacogenomics have received international recognition. The Journal of Prospective Health Care’s Kevin Chen spoke with Dr. McLeod about how he became interested in pharmacogenomics, the translation of scientific research into policy, and the future state of personalized medicine. Collapse Publication Eric J Peters, Howard L McLeod Editorial in Pharmacogenomics, November 2008, Vol. 9, No. 11, Pages 1573-1577.
"Another concern for pharmacogenomics studies is that whole-genome arrays may not capture known, functional pharmacogenomic variation..." Collapse Publication Jane L. Yen; Howard L. McLeod This article describes and evaluates the clinical utility of currently available laboratory tests for deficiency of dihydropyrimidine dehydrogenase (DPD), a key enzyme in the breakdown of the widely used anti-cancer drug 5-fluorouracil (5FU). Cancer patients who are deficient in DPD often experience severe, even lethal, side effects from the administration of 5FU, and require lower doses of the drug. Promising new approaches are being developed that may enable individualized 5FU dosing based on testing for DPD deficiency. Collapse Publication C. Ryan Miller, MD, PhD, and Howard L. McLeod, PharmD Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects. A major goal of this effort in cancer chemotherapy is the avoidance of severe, potentially life-threatening drug toxicity for patients. Genetic polymorphisms in drug-metabolizing enzymes and other molecules involved in drug disposition are responsible for much of the interindividual differences in the toxicity of many chemotherapy agents. This review will discuss clinically relevant examples of gene polymorphisms that influence toxicity and the experimental tools that have been utilized for discovering toxicity-related polymorphisms. Collapse Publication David Gurwitz & Howard L McLeod In this editorial, the authors summarize recent studies showing that 6-7% of hospital emergency room visits leading to hospitalization are due to adverse reactions of patients to drugs, and they make the case for using genetic testing prior to prescribing to reduce these adverse drug event rates. Collapse Publication Howard McLeod In an interview, Dr. McLeod describes how the science of pharmacogenomics will help to characterize tumors at a molecular level, leading to the ability to select the most appropriate therapy for individual patients. He discusses how this will change the practice of oncology, and some of the challenges that lie ahead in implementing these changes. Collapse Publication Howard L. McLeod, PharmD; Janelle M. Hoskins, PhD We live in a remarkable time, where multiple therapeutic options are available for most common diseases. However, the selection of the optimal medication for an individual patient is still problematic. Indeed we select the “right” initial therapy only half the time. In addition, adverse events remain unpredictable. Lastly, the expense of many new biological therapies, including those for IBD, is such that even wealthy countries such as the U.S. cannot afford to treat all patients. The completion of the human genome has enabled the development of clinical tools for patient evaluation.... Collapse Publication Lanfear, David E. MD, FACC; Spertus, John A. MD, MPH, FACC; McLeod, Howard L. PharmD Patients who have had heart attacks are usually treated with beta-blockers, drugs that block the action of proteins called beta-adrenergic receptors, but treatment outcome is variable and many patients still die. A genetic test for variants in one of the beta-adrenergic receptor genes, ADRB2, seems to predict the risk of mortality in these patients. The authors suggest that testing for these genetic variants may help to guide therapy in heart attack patients. Collapse Publication Dan M. Roden, MD; Russ B. Altman, MD, PhD; Neal L. Benowitz, MD; David A. Flockhart, MD, PhD; Kathleen M. Giacomini, PhD; Julie A. Johnson, PharmD; Ronald M. Krauss This review article provides a NIH Pharmacogenetics Research Network overview of the mechanisms underlying variation in individual response to drug therapy, how an individual’s genetic makeup contributes to that variation in response, and the challenges that must be overcome to fully characterize the genetic and genomic basis of variable response to drug therapy, and to translate that knowledge into improvements in drug development and the individualization of drug therapy. Collapse Publication David E Lanfear, Joshua M Stolker, Sharon Marsh, Michael W Rich & Howard L McLeod The level of B-type natriuretic peptide (BNP) in a patient’s blood is a key diagnostic and prognostic factor in patients with heart failure, and a synthetic form of this hormone is used to treat heart failure. Genetic variation in natriuretic peptide receptor (NPR)3 was shown to have an effect on cardiac filling pressure. Testing for this variation may improve the diagnostic and prognostic interpretation of BNP levels, and allow for individualizing BNP therapy for heart failure. Collapse Publication |
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