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New drug safety model unveiled as Merck shells out for Vioxx

By Mike Nagle , 12-Nov-2007

A new 3D model of the human liver that even has its own blood supply could pump new life into drug safety tests by predicting problems earlier and cut down on animal experiments.

The team of researchers from the Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Germany, have stitched human liver cells to a piece of pig intestine to use as a 3D model in the early stages of drug development.

 

 

 

Despite the huge amounts of money the pharma industry ploughs in safety tests, the majority of drugs still fail clinical trials in humans and liver toxicity is one of the main reasons. Drugs are currently tested in animals and/or in human cell cultures, but this new system could reduce the number of animal experiments needed.

 

 

 

It also might predict drug problems both more accurately and earlier in the development process, which in turn could save the drug industry billions.

 

 

 

What sets this model apart from other 3D scaffolds is that the artificial tissue possesses a functional network of blood vessels - it is a vascularised liver model. However, some of the rival products are entirely animal free, such as ReInnervate's, which uses a highly porous polystyrene scaffold to grow HepG2 liver cells or Invitrogen's AlgiMatrix system that has a macroporous alginate sponge structure.

 

 

 

"The model enables us for the first time to bring drugs into physiological contact with cells just as in the human body, and to analyze the resultant breakdown products after they have been transformed by the cells," explained Professor Heike Mertsching of the IGB.

 

 

 

To create the testing system, the scientists first take a piece of a pig's small intestine, including an artery to supply the blood and a vein to carry it away. Then they remove the animal cells until all that remains besides the proteins of the connective tissue layer are the tubes of the vascular system.

 

 

 

This is then lined from the inside with human endothelial cells, as in real-life. As soon as artificial blood begins to circulate in the vascular system, cells of all kinds of organs can grow on the matrix. In fact, IGB researchers are also generating 3D cell systems with skin and intestine cells for wound healing and infection tests as well as for skin cancer research.

 

 

 

Since the tissue has its own blood circulation system, it can be kept alive in a bioreactor for weeks at a time. A computer controls the arterial pressure, the temperature and the flow speed.

 

 

 

In the 3D model, nutrients, oxygen and the drug ingredient under test are transported through the artery into the artificial liver. The liver then breaks down the various compounds and the vein carries away the metabolic waste products. As well as initial safety indications, long-term drug effects can also be investigated including what happens with repeated administration of a biologically active agent.

 

 

 

With all these tests, the overriding benefit is that the results should better reflect what would happen in humans. With more and more drugs being shelved well after drug regulators approve them and thousands of patients have taken them, it's not just money or animals that could be saved - human lives are at stake too and any step to improve safety testing is more than welcome.

 

 

 

In fact, the US Food and Drug Administration (FDA) has asked computer model experts Entelos to develop a 'virtual liver' that could help cut down on liver problems with new drugs. The tool will be used to develop biomarkers and preclinical assays in order to identify patients more at risk of liver injury and also more dangerous drug combinations.

 

 

 

Merck still counting the cost of Vioxx failure

 

 

Last Friday, Merck & Co. announced it had agreed to pay $4.85bn (€3.33bn) to resolve lawsuits filed against the pharma giant in the US related to heart attacks and strokes caused by its pain killer med Vioxx (rofecoxib).

 

 

 

The company will pay the money into a settlement fund for qualifying claims that enter into the resolution process, rather than to settle all the claims at once. The fund will cover more than 95 per cent of the current claims in the Vioxx litigation.

 

 

 

"This agreement...is consistent with our commitment to defend each claim individually through rigorous scientific scrutiny," said Bruce Kuhlik, general counsel of Merck.

 

 

 

"Under the agreement, there will be an orderly, documented and objective process to examine individual claims to determine if they qualify for payment."

 

 

This sentiment was echoed by the Chair of the Plaintiff's Negotiating Committee. Russ Herman said: "Creating a process to look at individual claims is the fairest way to efficiently and quickly provide payment to qualified claimants."

 

 

The agreement almost brings to an end more than three years of legal wrangling as victims of Vioxx tried to hold Merck to account, although the pharma giant said it "does not admit causation or fault" with this latest move.