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Research News Updates and Blogs

Research Update – Optimising drug regimens in paediatric liver disease using experimentally derived simulation tools

Researchers – Professor Amin Rostami, Dr Jill Barber and Mr Naved Alizai

Institution – University of Manchester

Background

In proteomics research, we quantify all the proteins, including the proteins that metabolise (change into a form that can used by your body) and transport drugs in a tissue of interest.

We can use this information to build computer-based avatars (also known as virtual twins) representing patients or groups of patients. Virtual clinical trials can be conducted on these avatars in circumstances where it would be unethical or impractical to perform trials on patients. These trials normally relate to dose-adjustment, and might include, for example, determining the best dose of pain medication for children with biliary atresia.

In this project, we set out to understand how the proteins that metabolise and transport drugs in the livers of biliary atresia patients differ from those of healthy children.

It is impossible to obtain liver tissue from very young healthy children, but we can obtain it from children who have died from factors other than liver disease. Children with biliary atresia typically undergo a surgical procedure (the Kasai procedure) at a very young age which yields small amounts of liver tissue that can be used for research. Thus, we have been able to compare the protein profiles of 25 patients with biliary atresia to 22 children with no liver disease.

Findings

The analysis has shown that, in general terms, biliary atresia results in a child’s liver failing to develop a mature enzyme profile. This means that many drugs cannot be metabolised normally and the implications will vary from drug to drug.

We have shown that the enzyme responsible for paracetamol toxicity (cause of side effects when taking large doses) is much reduced in biliary atresia which may allow larger doses of this drug to be given safely than in healthy infants. However, there are also several drugs transporters which are present at relatively high concentrations in biliary atresia. The significance of this finding is not yet clear; it may reflect the body attempting to compensate for the disease.

There have been five scientific articles resulting from this research so far.

Possible next steps

Next steps include building virtual twins of biliary atresia patients, and conducting virtual clinical trials, particularly of the effect of paracetamol on biliary atresia patients. Potential patient benefits are in dose adjustment. We would expect some drugs to require lower doses in biliary atresia patients, but paracetamol may be tolerated at higher doses, allowing more effective pain medication. This needs to be tested. It is also possible to quantify other proteins of interest using the data collected, and to determine whether other metabolic pathways are affected by biliary atresia. The data has been deposited in a public repository, where it is available for future research.

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