BIOTECH & LIFE SCIENCES
How OOC can reduce DILI in drug development
Biotechnology company CN Bio is helping drug developers reduce their costs and time to market
D
rug-induced liver injury (DILI) is a common cause of drug withdrawal during late drug development as well
as post-approval. The liver, a primary site of drug metabolism, is particularly susceptible to drug-induced injury. However, DILI can occur through several pathways, each involving diff erent mechanisms. Intrinsic DILI is generally caused
when a drug, or its metabolites, cause damage at high doses. It poses the least risk and is the easiest to predict using traditional approaches owing to its dose-dependency and early onset. Traditional in vitro and in vivo animal studies are less able to predict more complex indirect or idiosyncratic eff ects that are latent in onset. The former is generally mechanistically related to the pharmacodynamics of the drug causing immune system, or metabolic eff ects, with some
28
www.scientistlive.com
dose-dependency. The latter is more unpredictable and is often driven by genetic predisposition or underlying disease. These risks can pass undetected through development and early clinical trials, causing fi nancial and reputation losses upon attrition. This poses the question - how can preclinical workfl ows be modernised to reduce DILI risk?
HOW UNDERSTANDING THE MECHANISM OF TOXICITY REDUCES RISK The safety toxicology toolbox requires modernisation through humanisation to understand how DILI is induced. Identifying potential issues earlier provides an opportunity to perform exploratory investigations to unlock the mechanism behind the cause. Previously, unlocking the cause has proven diff icult as maintaining the key
phenotypic and functional attributes of primary human hepatocytes is notoriously challenging. Now there is a path forward that off ers the potential to recover good drugs by engineering out the fl aws, terminating programs before the clinic, or delivering the foresight to manage liabilities and proceed with caution.
HUMANISED NEW APPROACH METHODOLOGIES (NAMS) Liver-on-a-chip technology, or liver microphysiological systems, off er a sophisticated platform for studying DILI with greater accuracy and relevance to human physiology. These advanced in vitro NAMs replicate the complex 3D structure of the liver, including the arrangement of primary human hepatocytes and non-parenchymal cells, which are
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52
