INDIGO Biosciences Blog

Cell-Based Assays in Preclinical Drug Development

December 8, 2020

The assessment of a drug candidate’s cross-activity with human xenobiotic-sensing receptors provides important early indications of that drug’s potential for downstream drug-drug interactions or other toxicology concerns. Prior to moving into human trials, preclinical studies utilize animals as human surrogates to assess a drug’s pharmacokinetic and toxicologic profiles. A wide range of animal models are used in preclinical studies for drug discovery including mice, rats, dogs, zebrafish, rabbits, and non-human primates. In research, these animals are used because they are orthologs. Orthologs are animals of different species that share genes that evolved from a common ancestor and have retained a similar function to those genes in humans.


Preclinical Ortholog Testing Requirements

Though animals have been used in biomedical research for centuries, federal regulations requiring safety testing on animals only began in 1938 with the introduction of the Federal Food, Drug, and Cosmetic Act. The FDA, charged with oversight and approval of new drugs, created guidance documents and procedures which require preclinical data from animal studies to review whether a potential drug is reasonably safe for initial testing in humans. The FDA’s guidance documents and procedures are used to help researchers and regulators better understand a compound’s toxicity and safety profile to prevent possible off-target harmful events in humans during clinical trials. Even with the guidance from the FDA and successful preclinical testing, however, almost 90% of candidate drugs will fail in the first stage of clinical trials. If you have never heard this statistic before, you may be wondering why that percentage is so high.


Success during early stage clinical trials is heavily dependent on selecting the right animal model that allows for the assessment of target validity and can predict a specific compound’s clinical efficacy. These animal model studies are often confounded by the fact that ligand preferences and response dynamics can vary dramatically between the human receptor and corresponding ortholog receptors, even with receptors of closely related species such as rat and mouse. This creates a challenge when selecting the most human-relevant animal model for preclinical studies. With the rising cost of in vivo trials, understanding the differences and similarities between different animal models and human systems is crucial before choosing the specific ortholog for in vivo trials.


Supplementing Animal Studies with in vitro Cell-Based Assays

To make the switch from animal to human studies more successful, the addition of reporter cell-based assays can help a researcher extrapolate results from animal preclinical studies to human clinical trials. Comparative in vitro testing of ortholog and human reporter cell-based assays against a panel of receptors can help researchers better understand this relationship before investing in expensive in vivo studies, by allowing them to extrapolate human reactions to a drug candidate. With animal models playing such a large role in efficacy and safety evaluations of new drugs, understanding the differences between human and the proposed ortholog model through in vitro reporter cell-based assays can help improve and shorten animal trials and, in turn, clinical outcomes.


INDIGO is a leading provider of all-inclusive cell-based nuclear receptor assays. INDIGO’s ortholog kits and services can help make the transition from animal to human trials more successful. INDIGO’s cell-based assays can also be used to understand off target effects post trial. Learn more about INDIGO’s portfolio of ortholog kits and services.

Need help choosing the right ortholog model before beginning animal testing or looking to understand off target results post trial? Request information from the team at INDIGO Biosciences and learn more about INDIGOs suite of assays and research solutions.


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