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Pfizer Uses HCA for Hepatotox Assay, Seeks to Expand Tox Prediction Toolbox

SAN FRANCISCO — Pfizer researchers have used high-content imaging to develop a cellular hepatotoxicity screen that it will use for certain in vitro drug-development studies.
Pfizer’s existing toxicology portfolio comprises micronucleus assays and phospholipidosis assays. Now it plans to add to this mix hepatotoxicity assays, which will enable the company to focus narrowly on the way a single organ responds to drug candidates.
The development of the assay is particularly noteworthy for Pfizer after severe cases of hepatotoxicity linked to two of its drugs in recent years compelled the US Food and Drug Administration to issue a public health advisory for one and withdraw the other.
The first drug was the antibiotic Trovan. In 1999, one year after it approved the drug, the agency issued a letter to physicians cautioning that six patients died using the drug, and three patients needed liver transplants during a one-year period.
The second drug was the diabetes treatment Rezulin. The drug was approved in the US in 1997 and pulled from the market in 2000 after an FDA advisory committee concluded that it poses a greater risk of severe liver toxicity than other drugs in its class.
Speaking during the High-Content Analysis 2008 conference, held here this week, Arthur “Russ” Smith, a discovery toxicologist and scientist for Pfizer Global Research and Development, said that the screen is based on approximately 700 compounds.
He said the number of compounds will enable the drug maker “to maximize sensitivity to capture hepatotoxicity without generating false positives.”
Commenting on the robustness of the assay, Smith said that some drugs found to be hepatotoxic in the initial screen were also observed to be hepatotoxic in animal testing. He declined to elaborate.
He said the next step for Pfizer is “to look at the classes of drugs we missed and to build new assays as part of a toolbox of secondary screens that address specific mechanisms relevant to toxicity, such as the inflammatory state in the body,” said Smith.

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