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Advances in Predictive Human Toxicity – Cryoperserved Human Hepatocytes
Adverse drug reactions are a big problem in pharmacy and medicine. With a striking death-toll of nearly one quarter of all disease related deaths worldwide, it certainly is a big target for innovative pharmaceutical technologies to tackle. Models able to predict drug efficacy and toxicity in humans, cost-effectively and in a less time-consuming way are a big outstanding need in all biomedical and pharmaceutical research.

“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 blames the bigger part of clinical trial failures and patient death catastrophes on the discordance between animal models and human in vivo models. He expresses his concerns with the pre-clinical animal model data safety. “There may be species-specific differences in toxicity, resulting in discordance of results between laboratory results, animal, and human findings.”

Liver metabolisms differ greatly between species, and human livers operate very differently than most mammal livers. A drug is metabolized by the liver, producing detoxified (less toxic or benign) or either metabolically activated (more toxic) compounds, and due to the difference in liver metabolisms in humans and other species, this data cannot always translate from animal model systems into human systems.

There is also the phenomenon of idiosyncratic toxicity to consider. This represents the different reactions of several individuals within a species, with differing toxicity from individual to individual.

Idiosyncratic toxicity is a human-specific occurrence, with an instance lower then 1:5000, and has thus proven impossible to study with clinical trials, let alone animal models. Current trends in the pharmaceutical world actively discourage animal testing, with European regulatory agencies banning animal testing for the cosmetic industry. So far, many drugs that have passed animal testing have been withdrawn from the market, due to safety concerns.

An emerging trend and standard in drug testing is instead used. Human pluripotent stem cells are being used to induce the creation of cellular models for drug testing, such as miocardiocytes, glial cells and diseased neurons. Additionally, tissue engineering technologies have yielded new systems for drug testing, consisting of three dimensional tissue systems, modeled for patient implantation to test and track drug toxicity effects. Also, lab-on-a-chip technologies are also available, providing silica based and in vitro model systems for screening drug toxicity.

At the “International Conference on Predictive Human Toxicity and ADME/Tox Studies” this year, many new technologies have been discussed, chief among them the Cryopreserved Human Hepatocytes as viable models systems for testing drug toxicity in vitro.

“We now have optimized the isolation, culturing, and cryopreservation of human hepatocytes to retain high viability and, most importantly, retention of drug metabolism capability similar to the human liver in vivo,” said Dr. Li. “These cryopreserved human hepatocytes now represent the gold standard for human drug metabolism research,”

Dr. Li and colleagues have, in cooperation with the FDA, worked on a project aiming to develop an in vitro assay for the identification of drugs that cause liver failure.

“Using the ratio of reactive oxygen species: cellular ATP content as the endpoint, we were able to identify drugs that are known to cause severe liver failure (drug induced liver injury, or DILI) with a specificity and sensitivity of near 90%,” he said. “This novel assay complements the assays that we have previously developed with human hepatocytes such as the Metabolism Comparative Cytotoxicity Assay (MCCA) or the Cytotoxic Metabolic Pathway Identification Assay (CMPIA).” Dr. Li adds.
This new approaches have been developed to measure the hepatic drug toxicity in hepatocyte metabolism. Indeed, a big part of drug toxicity is the hepatic toxicity, considering that the liver receives the biggest battery of substances after oral administration, and the liver can react with a high variety of substances to create highly toxic metabolites from relatively harmless substances, an effect that can hardly be predicted without model system testing.

“We have developed an additional assay with the IdMOC (Integrated Discrete Multiple Organ Co-culture) system with which we can detect toxicity to nonhepatic cell types by toxic metabolites formed by hepatocytes. We believe that our battery of assays would improve our ability to identify drugs and drug candidates with human-specific toxicity that cannot be detected using the classical toxicological approaches with laboratory animals.” – says Dr. Li.

He proposes his system be used as first level screening of drug candidates, as to critically reduce possible mistakes and oversights in drug toxicity research.

Data obtained from transcripts of the “International Conference on Predictive Human Toxicity and ADME/Tox Studies”
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