Preclinical in vitro testing for ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties has come a long way in the decade since it became an important consideration in the discovery process. But it still has a long way to go.
“Before the late 1980s to early 1990s, ADME testing was not a significant component of the drug discovery effort,” noted Robert J. Guttendorf, Ph.D., vp, pharmacology and experimental therapeutics, Sequoia Pharmaceuticals.
“As a result, poor ADME was a significant contributor to attrition of drug candidates. As higher-throughput methods allowed us to be more involved in the drug discovery process, by the 2000s we were able to optimize ADME properties while simultaneously optimizing intrinsic pharmacologic activity. We became an integral part of the discovery effort, enabling teams to solve two key problems in parallel.”
Dr. Guttendorf noted that, while eventually trimming attrition due to poor ADME from 40% to 10% is a great thing, “drug discovery is not working by the old blockbuster standard anymore. Overall attrition of drug candidates is still 90 percent, and the burden has merely been shifted from ADME to toxicology and pharmacology. But since pharmacokinetics is crucial to optimizing pharmacology and toxicology in vivo, we still have significant work to do.”
There is no doubt that there are still challenges. Hinnerk Boriss, Ph.D., CEO at Sovicell, observed that “the bottleneck is in the tox part of the field. It’s difficult to come up with meaningful tox assays, because they only run a short time, and PK typically acts over the long term. So it’s hard to tell long-term toxicity and whether it has any relativity to long-term, low-level toxicity.”
At the “Predictive Human Toxicity and ADME/Tox Studies” meeting, researchers had the opportunity to assess ADMET’s impact on the quality of leads that are nominated for clinical development, as well as see what new tools and methodologies are becoming available.
“ADMET is no longer a nice-to-do tool. It has become an integral part of drug discovery and development,” noted Katya Tsaioun, Ph.D., president, Apredica. “New ADMET tools are being developed and validated. These tools are more predictive of human mechanisms of toxicities and metabolism. A lot of interesting work is being done in ADMET right now to allow organ-specific (particularly hepato- and cardio-) toxicity, and the mechanistic modes of toxicity to be predicted early in the lead-optimization process.”