BIOTECHNOLOGY
DATA TRANSLATION F
How in-vitro to in-vivo translatability (IVIVT) of preclinical data is improved with Organ-on-a-chip technology
ollowing the passing of the FDA’s Modernisation Act 2.0 in 2022, the use of New Approach Methodologies
(NAMs), including Organ-on-a- Chip (OOC), is now supported and encouraged by the world’s largest regulator for evaluating drug safety and eff ectiveness in place of animal testing, where appropriate. Despite this progress, replacing animals in safety testing is challenging and likely to be slow, since animal models provide many organ-specifi c readouts that are not fully reproductible in vitro. However, there are contexts of
use where OOC data can be used to supplement animal data and improve safety risk assessments through better informed decisions about human- relevant safety – especially for the liver. Most medications are metabolised in the liver, which makes it susceptible to adverse drug reactions. A publication by Singh et al., 20251 highlights that
The PhysioMimix Single-organ System and Multi-chip Liver 12 plates
Most medications
are metabolised in the liver, which makes it susceptible to adverse drug reactions
55 medications were approved by the US FDA in 2023, with 22 (40%) having evidence of liver toxicity in the drug label or clinical trial results. So, for some, why was DILI only identifi ed in human studies? Two retrospective reviews found
the positive concordance between liver toxicity in animal tests and clinical trials was 55% (Olson et al., 2000)2 and 33% (rats), 27% (dogs), and 50% (monkeys) (Monticello et al., 2017)3. The main reason relates to interspecies diff erences in drug disposition, however, there are other contributing factors as reviewed by Taylor et al., 20254. This problem is further exacerbated by newer human- specifi c drug modalities for which animal testing is less suited. These reasons necessitate the need for pre-clinical toolbox modernisation with NAMs, including OOC, to deliver improved in-vitro to in-vivo translatability (IVIVT).
HOW OOCS IMPROVE IVIVT AND HOW TO DEMONSTRATE THEIR CAPABILITY Human liver-on-a-chip models are utilised to predict and gain a mechanistic understanding of drug induced liver injury (DILI). Their enhanced human relevance provides a means to overcome the limitations of animal models, which can miss some instances of idiosyncratic DILI, plus they provide a viable path forward for new drug modalities. One approach used by OOC vendors to prove their enhanced translatability is by studying fl awed drugs that made it to market. However, unless unsuited, preclinical
testing involves testing in animal models. Data discrepancies between human in-vitroand animal in-vivo studies make the fi nal assessment of drug safety in humans challenging. So, do we need to take a step back and more eff ectively translate data
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