In 1993, five people died as a result of a clinical trial into the drug fialuridine. The drug had previously passed preclinical screening in animal trials. Now, a new study finds that these deaths could have been averted if a chimeric mouse trial had been part of the routine screening.

Prior to the clinical trial, fialuridine had passed toxicology studies in mice, rats, dogs and primates. This kind of animal testing is used to see whether the drug is likely to work and to see if it has any short- or long-term toxic effects, such as damage to the liver.

When drugs pass the animal testing, they proceed to phase I clinical trials, where a small group of healthy human volunteers are administered the drug to identify possible side effects.

Fialuridine had passed to a phase II clinical trial, which is when the drug is given to a larger number of patients in order to evaluate the effectiveness of the drug.

During the first 8 weeks of the phase II clinical trial, which involved 15 human participants, results were promising. Very few adverse effects had been recorded, and the new drug was proving to be effective at fighting hepatitis B virus.

But by week 13, the trial had been cancelled. Serious complications – hepatic failure, lactic acidosis and pancreatic failure – had occurred in seven of the patients. Five of these patients died, and the remaining two required emergency liver transplants.

Fialuridine had not shown any indication that it could cause human liver damage (hepatoxicity) in the preclinical testing on mice, rats, dogs and primates. But it now seems that the way a nucleoside transporter works in the mitochondria of humans is different to other animals. This is why the animal testing did not raise any concerns over hepatoxicity.

A team of Japanese and American researchers investigated whether an alternative test could have detected the hepatoxic properties of fialuridine before the clinical phases of the trial. They publish their results in PLOS Medicine.

The researchers wanted to see if “chimeric mice” – mice with some human cells – could be used to detect the hepatoxicity. To do this, they devised a toxicology test using mice that had 90% of their liver cells replaced with human liver cells.

When these chimeric mice received the fialuridine, they began to display the same symptoms as the human participants of the 1993 trial. The mice became jaundiced and lethargic, and they had elevated transaminase and lactate levels – their livers were failing.

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The researchers wanted to see if “chimeric mice” – mice with some human cells – could be used to detect hepatoxicity.

To make sure that it was the fialuridine that was causing the liver failure, the researchers administered a drug called sofosbuvir to a second group of humanized mice.

Sofosbuvir is a similar drug to fialuridine, but has been tested in humans and does not cause hepatoxicity.

The mice who received sofosbuvir did not show symptoms of liver failure.

Although the humanized mice have an impaired immune system and so cannot show toxicity occurring via the immune system, in this case they showed that this drug causes damage to the liver – the organ used to “detox” the body. Therefore, scientists can extrapolate from this that the drug will also damage the livers of humans.

The technology to produce chimeric mice did not exist back in 1993, when the fialuridine phase II trial took place. There is also no current requirement to use them in preclinical evaluations.

Dr. Gary Peltz, one of the authors of the new study, told Medical News Today: “The results presented in this paper represents my attempt to demonstrate that drug safety could be improved by the use of chimeric mice with humanized livers in the preclinical assessment of drugs.”

“The major reason that chimeric mice are not used – as they should be – as part of the preclinical evaluation of drugs,” continued Dr. Peltz, “is because the regulatory agencies do not require them in the preclinical evaluation of candidate drugs.”

Dr. Peltz argued that “the [Food and Drug Administration] needs to become a more ‘rapid adopter,'” more pro-actively testing and including new technology into drug evaluation that could improve drug safety. He concluded:

This paper represents an inflection point for the chimeric mouse field. It provides the first clear demonstration that studies performed in chimeric mice could improve drug safety, which in this case would have averted a tragedy caused by a human-specific drug toxicity.”