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May 1, 2009 (Vol. 29, No. 9)

ADMET Increasingly Integral to Discovery

Evolving Technology and Regulations Rapidly Advance a Formerly Extraneous Tool

  • Blood-to-Brain Absorption

    “Sovicell has e a chemical model based on natural lipids that gives reliable estimates of the freely available drug in brain,” noted Dr. Boriss. “In fact, you get both an estimate of the brain-to-plasma distribution and the fraction of drug that is not bound to brain tissue. Due to its low price point, it can be applied in early stages of research before committing to particular structure.”

    Dr. Boriss presented one of Sovicell’s plasma protein binding models, the TRANSIL High Protein Binding assay, “which addresses difficult to handle compounds. This relates to compounds which bind to 99 percent or more, or which are excessively sticky,” Dr. Boriss explained. “With standard assays, you run into analytical issues since there is so little compound left to quantify. TRANSIL is an assay that not only works in high-throughput format, but is also convenient, as it works well with highly lipophilic compounds and minimizes any bias due to unspecific binding.”

  • Recent FDA Guidelines

    “At Apredica, we often find that drug-discovery teams are confused about how and when to address preclinical ADME-Tox issues and about what the FDA guidance call for,” Dr. Tsaioun said. “I find that, in working with them, it’s important to review the clinical implications, starting with target product profile, to do what-if scenarios, to explain why the FDA would care, and to bring up the importance of following protocols that are developed following FDA guidelines.

    “One of the most important things to understand about ADMET,” Dr. Tsaiou added, “is that one needs to start evaluating the drug-like properties of drug candidates early enough so that the discovery team has choices and is not committed to one molecule. Don’t get attached to a molecule. Fail fast and focus on the candidates most likely to succeed. This knowledge can save you time and resources.

    “In the end, the more you know about your compound’s ADMET properties, the less complex or expensive your IND package is going to be.

    “ADMET assays don’t kill compounds, decision-making groups do,” concluded Dr. Tsaioun.

    “For those groups to make good decisions about compounds they need to closely collaborate and communicate. Biology must talk to chemistry and  discovery scientists must communicate with development people, otherwise, good compounds get terminated and bad compounds are advanced for reasons that are not always scientific.”



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