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Genetic polymorphisms in ABC (ATP-binding cassette) transporter genes are associated with differential responses to chemotherapy in various cancers including pancreatic cancer. In this study, four SNPs in the ABCB1, ABCC1, and ABCG2 genes were investigated in normal and pancreatic cancerous specimens. The expression of the three transporters was also analyzed. The TT genotypes of G2677T and C3435T in ABCB1 gene were associated with lower risk of developing pancreatic cancer (P = 0.013, OR = 0.35 and P = 0.015, OR = 0.29, resp.). To our knowledge, this is the first report of the common polymorphisms in the ABCB1 gene affecting the genetic risk of developing pancreatic cancer. Moreover, the expression of ABCB1 in 2677TT and 3435TT carriers was lower compared to the wild-type homozygotes and heterozygotes. A cell viability assay, using standard pancreatic cancer cell lines, revealed that the ABCB12677TT-3455TT haplotype was more sensitive than the other haplotypes to gemcitabine. Conclusion. Polymorphisms in ABCB1G2677T and G3435T were associated with differential susceptibility to pancreatic cancer and may predict responses to chemotherapy. [ABSTRACT FROM AUTHOR]

Therapeutic proteins (TPs) may affect the disposition of drugs that are metabolized by cytochrome P450 (CYP) enzymes, as is evident from a review of data in recently published literature and approved Biologic License Applications. Many TPs belonging to the cytokine class appear to differentially affect CYP activities. Cytokine modulators may affect CYP enzyme activities by altering cytokine effects on CYP enzymes. The alteration in CYP enzyme activities seems to result from changes in transcription factor activity for CYP enzyme expression or changes in CYP enzyme stability, which have been observed during altered immunological states such as infection and inflammation. Human growth hormone also appears to differentially affect CYP activities through unknown mechanisms. Because TP-drug interaction research is an evolving area, limited information is available during drug development on TP-drug interactions mediated by CYP inhibition or induction. The authors of this review suggest that effort be made to understand TP-drug interactions for the safe and effective use of TPs in combination with small-molecule drugs. [ABSTRACT FROM AUTHOR]

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling. [ABSTRACT FROM AUTHOR]

Warfarin is a challenging drug to accurately dose, both initially and for maintenance, because of its narrow therapeutic range, wide interpatient variability, and long list of factors that can influence dosing. Two million people in the United States are initiated on warfarin therapy annually, and this number is steadily increasing because of the increase in number of eligible patients. Recently, warfarin was reported to be the fourth leading cause of adverse events. The U.S. Food and Drug Administration recognizes that the adverse event rate of warfarin can be improved through better initial dosing, because many of the serious adverse events of warfarin occur soon after starting treatment. A substantial number of studies demonstrate that common variants of two genes, VKORC1 and CYP2C9, along with other nongenetic factors, correlate significantly with warfarin dosing. The genotypes of VKORC1 and CYP2C9 alone account for nearly 3 times more of the variability (∼30%) in warfarin dosing than do age, weight, gender, and other clinical factors combined (∼12%). Therefore, the purpose of this report is to review the current recommendations for warfarin therapy that involve genetic testing. [ABSTRACT FROM AUTHOR]

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA'S current under- standing of drug interactions (http://www.fda.gov/cder/drug/druglnteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling. [ABSTRACT FROM AUTHOR]

Serious drug-drug interactions have contributed to recent U.S. market withdrawals and also recent nonapprovals of a few new molecular entities. Many of these interactions involved the inhibition or induction of metabolizing enzymes and efflux transporters, resulting in altered systemic exposure and adverse drug reactions or loss of efficacy. In addition to drug-drug interactions, drug-dietary supplement and drug-citrus fruit interactions, among others, could also cause adverse drug reactions or loss of efficacy and are important issues to consider in the evaluation of new drug candidates. This commentary reviews (1) the current understanding of the mechanistic basis of these interactions, (2) issues to consider in the interpretation of study results, and (3) recent labeling examples to illustrate the translation of study results to information useful for patients and health care providers. [ABSTRACT FROM AUTHOR]

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues. [ABSTRACT FROM AUTHOR]

A new report from an international consortium provides comprehensive scientific recommendations for studies of transporter-related drug interactions in drug development. [ABSTRACT FROM AUTHOR]

In recent years, major research consortiums spanning academia, industry and government have been founded to address key challenges in basic and translational research. This month we feature two scientists with key roles in fostering such collaborative, interdisciplinary research activities. [ABSTRACT FROM AUTHOR]