Testing the biological activity of pharmaceutical drugs, agro-chemicals and other xenobiotics on human relevant systems has increasingly become an important regulatory requirement to make a go or no-go decision (drug selection and risk assessment) before proceeding to a clinical trial.
In an API industry, out of the 100% compounds that reach the pre-clinical stage, only 3-5% reach the phase 1 of clinical trials1. At pre-clinical stage the number of compounds drastically reduces from 10,000-20,000 to 20. Therefore, identifying a safe, potent, and efficacious drug requires thorough pre-clinical testing, which evaluates aspects of pharmacodynamics, pharmacokinetics, and toxicology in in-vitro and in-vivo setting2.
In the R&D department of drug discovery, judicious use of time and costs is of utmost importance given the low chances of arriving at a candidate molecule which can potentially enter human clinical trials. Keeping this in mind, it is a wise choice to start by filtering out the leads using simpler and ethically less-critical methods to proceed towards the pipeline.
In-vitro testing is one such ethically less-critical approach towards filtering out the leads which produces dependable results in a short span of time. It allows screening of multiple compounds in a short span of time. The recent progress in this space makes in-vitro testing a lucrative strategy to start the pre-clinical testing with the use of – Stem cells – Embryonic & adult stem cells, and Induced Pluripotent stem cells (iPSCs), 3D Tissue models, Organ-on-chip systems and multi-organ-chip, In-silico models, and Spheroids and Organoids.
Our partner Crown Bioscience, Inc. has developed their proprietary database, OrganoidBaseTM featuring the PDX-derived organoid (PDXO) tumour models and patient derived organoids (PDO) to improve predictivity. Crown Bioscience, Inc. created a suite of powerful 3D in-vitro imaging-based assays that recapitulate and quantify complex human biology in a robust and high-throughput imaging platform.
Though the advancements in in-vitro testing systems is intriguing and laudable, a void in monitoring the exact performance of a drug in micro-environment of an organ is a miss3. Fortuitously, we have the in-vivo testing approach to verify the results obtained from in-vitro or in-silico. In-vivo preclinical studies using research models like mice, rats, guinea pigs, rabbits etc., enable the researchers get one-step closer to the candidate molecule/ drug. The appropriate cellular and physiological conditions of a whole organism in research models4, make the results obtained from in-vivo testing validate the in-vitro studies performed and confidence to continue with clinical trials.
The complete visible effect of a compound/ product on a living organism like interactions, metabolism, and distribution via in-vivo testing5 can help researchers make informed decisions.
However, the traditional in-vivo testing systems though reliable, lack the ability to precisely replicate the interaction of the compounds with human tissues3 – a major obstacle that demands an advancement in the in-vivo testing space. To overcome this obstacle in in-vivo testing, our partner and global leader in research model breeding and distribution, Envigo RMS LLC, came up with Humanized genetically engineered mice models (hGEMMs) that can help study the interaction between human tissues and tumour cells. Some popular humanized research models available with Envigo RMS LLC include: hACE2 knockin mice & rats, hACE2/hTmprss2 double knockin mice, hTmprss2 knockin mice. The research use and application of these research models includes oncology, cardiovascular, infectious diseases, and COVID-19.
Stephen Covey’s advice from one of his bestsellers – “Begin with the end in mind” is also applicable to drug development. The goal in drug development is to successfully file an IND/NDA and its prescribed use in the clinic6. Considering how the benefits of in-vivo testing fills the gaps in in-vitro testing and vice-versa, it is a smart choice to recognize the vantage point of balance between the two testing types and advance your research.
References:
- Ranjita Shegokar, Chapter 2 – Preclinical testing—Understanding the basics first, Editor(s): Ranjita Shegokar, Drug Delivery Aspects, Elsevier, 2020, Pages 19-32, ISBN 9780128212226, https://www.sciencedirect.com/science/article/abs/pii/B9780128212226000026
- Honek, J. (2017). Preclinical research in drug development. Medical Writing, 26, 5-8.
- Yin L, Wang XJ, Chen DX, Liu XN, Wang XJ. Humanized mouse model: a review on preclinical applications for cancer immunotherapy. Am J Cancer Res. 2020 Dec 1;10(12):4568-4584. PMID: 33415020; PMCID: PMC7783739.
- Tian H, Lyu Y, Yang Y-G and Hu Z (2020) Humanized Rodent Models for Cancer Research. Front. Oncol. 10:1696. doi: 10.3389/fonc.2020.01696
- https://www.zeclinics.com/blog/differences-between-in-vitro-in-vivo-and-in-silico-assays-in-preclinical-research/
- Steinmetz, K.L., Spack, E.G. The basics of preclinical drug development for neurodegenerative disease indications. BMC Neurol 9 (Suppl 1), S2 (2009). https://doi.org/10.1186/1471-2377-9-S1-S2
Sai Supriya has a 2 year experience in academic research and fair exposure to transition into industry. She enjoys delving deep into the new developments in the biotech, pharma industry and collaborating with people. She is zealous and keen to direct her best strengths to the role by being receptive to new ideas and challenges.