Adverse drug reactions (ADRs) are the fourth leading cause of death worldwide. In the U.S. alone, 2.2 million serious ADRs are reported annually in the hospitalized population, with over 100,000 deaths.
Models that better predict a drug’s efficacy and a drug’s toxicity cost-effectively are the need of the hour.
“A major challenge of drug safety testing is that preclinical studies with laboratory animals are not always predictive of human safety,” said Albert P. Li, Ph.D., president and CEO of In Vitro ADMET Laboratories. Dr. Li cited the frequent clinical trial failures due to safety concerns with drug candidates that have been chosen based on preclinical animal safety data.
Dr. Li’s work suggests that “there may be species-specific differences in toxicity, resulting in discordance of results between laboratory results, animal, and human findings.” Liver metabolism differs greatly between other animal species and humans. For instance, as a drug is metabolized to a more toxic (metabolic activation) or less toxic (metabolic detoxification) compound, preclinical results with laboratory animals may not always translate into applications for humans.
The involvement of metabolism in toxicity may also lead to individual differences in toxicity, which may explain the phenomenon of idiosyncratic toxicity, according to Dr. Li.
Idiosyncratic drug toxicity is human-specific, occurring as a rare event (<1/5,000) and therefore, impossible to study in clinical trials or experimental animals. In fact, current trends suggest that regulatory agencies actively discourage animal testing in research. Europe has banned the use of animal testing for all cosmetics. Indeed, many drugs have been withdrawn from the market due to safety concerns.
Instead, human cells are being used (e.g., induced pluripotent stem cells [iPS]) to yield cardiomyocytes or Parkinson’s neurons. As well, tissue engineering efforts have created three-dimensional tissue equivalents designed for transplantation into patients, and screened for toxicity. In vitro and in silico modeling of tissues and diseases using lab-on-a-chip technologies are available. As agencies such as the NIH, FDA, and the DARPA seek new ideas and proposals, researchers have come up with cutting-edge solutions.
At the “International Conference on Predictive Human Toxicity and ADME/Tox Studies”, experts from the biotech and pharma industry discussed recent advances toward accurately predicting human toxicities and screening early in the drug discovery process.