ADMET

/Tag:ADMET

De-Risking Drug Discovery with ADDME — Avoiding Drug Development Mistakes Early

Katya Tsaioun and Mary Jacewicz

The advent of early Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening has increased the elimination rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and why it has become so important in drug discovery and development. Assays that have been developed in response to specific needs, and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of toxicity, are discussed. The paper concludes with the authors’ forecast of new models that will better predict human efficacy and toxicity.
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Toward Preclinical Predictive Drug Testing for Metabolism and Hepatotoxicity by Using In Vitro Models Derived from Human Embryonic Stem Cells and Human Cell Lines — A Report on the Vitrocellomics EU-project

Carl-Fredrik Mandenius, Tommy B. Andersson, Paula M. Alves, Christine Batzl-Hartmann, Petter Björquist, Manuel J.T. Carrondo, Christophe Chesne, Sandra Coecke, Josefina Edsbagge, J. Magnus Fredriksson, Jörg C. Gerlach, Elmar Heinzle, Magnus Ingelman- Sundberg, Inger Johansson, Barbara Küppers-Munther, Ursula Müller-Vieira, Fozia Noor and Katrin Zeilinger

Drug-induced liver injury is a common reason for drug attrition in late clinical phases, and even for post-launch withdrawals. As a consequence, there is a broad consensus in the pharmaceutical industry, and within regulatory authorities, that a significant improvement of the current in vitro test methodologies for accurate assessment and prediction of such adverse effects is needed. For this purpose, appropriate in vivo-like hepatic in vitro models are necessary, in addition to novel sources of human hepatocytes. In this report, we describe recent and ongoing research toward the use of human embryonic stem cell (hESC)-derived hepatic cells, in conjunction with new and improved test methods, for evaluating drug metabolism and hepatotoxicity. Recent progress on the directed differentiation of human embryonic stem cells to the functional hepatic phenotype is reported, as well as the development and adaptation of bioreactors and toxicity assay technologies for the testing of hepatic cells. The aim of achieving a testing platform for metabolism and hepatotoxicity assessment, based on hESC-derived hepatic cells, has advanced markedly in the last 2–3 years. However, great challenges still remain, before such new test systems could be routinely used by the industry. In particular, we give an overview of results from the Vitrocellomics project (EU Framework 6) and discuss these in relation to the current state-of-the-art and the remaining difficulties, with suggestions on how to proceed before such in vitro systems can be implemented in industrialdiscovery and development settings and in regulatory acceptance.
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