1. Susman, Ed

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HOLLYWOOD, Fla.-An oral antidote to life-threatening toxicity from the rare situation of fluorouracil (5-FU) overdose or hypersensitivity appears to be highly successful, researchers reported here at the National Comprehensive Cancer Network conference.

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The investigational drug, uridine triacetate, was successful in 97 percent-128 of 132-cases of 5-FU overdose caused by errors in dosing, infusion pump malfunctioning, or excess ingestion of oral 5-FU sources such as capecitabine, said Michael Bamat, PhD, Vice President of Research and Development at Wellstat Therapeutics Corporation in Gaithersburg, Md.


In the time since his poster study was presented in March, there have been five additional cases that came to the team's attention, Bamat said in a follow-up interview, and the treatment has been successful in 133 of these incidents.


He explained that usual treatment for 5-FU toxicity has been best supportive care, but unfortunately, historical data suggest that this strategy is often unsuccessful. In his poster presentation at the NCCN meeting, researchers determined that in a historical control group of 40 patients with 5-FU toxicity, just four patients achieved a complete recovery. The rest of these patients died. Information on dosages and outcomes for the historical 5-FU overdose cases were obtained from publicly available reports, he noted.


"These clinical data illustrate the serious, debilitating, and life-threatening nature of 5-FU overexposure and the need for safe, effective antidotal treatment."


Very Rare, but Accidents Do Occur

Asked for her opinion, Edith Perez, MD, Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, Fla., said, "The risk of 5-FU overdose is extremely low. All chemotherapy units should have carefully outlined procedures to prevent incorrect doses of chemotherapy being given to patients."


Nevertheless, accidental overdoses of 5-FU occur. Bamat cited National Institutes of Health estimates that 275,000 cancer patients are treated with 5-FU every year, and that 8,250 of these patients develop serious toxic reactions and that more than 1,300 patients die each year from 5-FU overexposure.


He said that about 60 percent of the cases that have been treated with uridine triacetate were caused by miscalculation or mismanagement of the intravenous delivery. Because 5-FU is administered at or near its maximum tolerated dose over one to four days, life-threatening or lethal toxicity can be caused by these pump-related errors, he said.


In addition, there are other patients who have dihydropyridimine dehydrogenase (DPD) deficiency and other forms of 5-FU elimination or hypersensitivity that can also result in serious or lethal toxicity following standard doses of infusional 5-FU or oral capecitabine. For example, unusual susceptibility to 5-FU can result in severe and sudden onset cardiac and/or neurological toxicities, he said, noting that 10 of the patients treated in his case series have been found to have DPD deficiency. Six children were included in the study.


Over-ingestion of capecitabine has also been a cause of overdose, including some cases in which patients attempted to commit suicide by ingesting capecitabine in lethal amounts.


Uridine, Bamat explained, is a direct biochemical antidote for 5-FU poisoning, but the drug has poor oral bioavailability, and complications during its infusion preclude use of uridine itself as a viable antidote. Hence, the researchers developed uridine triacetate as an orally available prodrug of uridine. Uridine triacetate is rapidly converted to circulating uridine by deacetylation.


The agent is administered at a dose of 10 grams every six hours for 20 doses in adults and at an equivalent dose of 6.2 grams/m2 every six hours for 20 doses. Treatment with uridine triacetate was initiated seven to 96 hours following the end of treatment with fluorouracil.


"Based upon data collected to date, uridine triacetate appears to provide clinical benefit to patients even in cases where a lethal outcome otherwise would have been expected," he said.


The patients in the study were treated after their physicians contacted the company to use the drug in a Food and Drug Administration-approved expanded access protocol for emergency use. Uridine triacetate was administered seven to 96 hours after 5-FU treatment was halted.


About half the patients were able to resume their chemotherapy regimens within three weeks after overexposure, Bamat reported. In addition, treatment with uridine did not appear to cause serious adverse events. The adverse events that did occur were considered mild, and many of the patients treated with uridine triacetate had no adverse events at all.


Uridine triacetate had previously received Orphan Drug designation as an antidote to treat patients at risk of excess 5-FU toxicity from both the Food and Drug Administration and the European Medicines Agency. Bamat said the company expects to file a New Drug Application for uridine by the end of the year.


A Phase III study is not possible in a treatment that is based on emergency overdose, he added. "When we submit our application for approval of uridine triacetate it will include the number of patients treated and their outcomes. We are continuing to treat patients under the expanded access program."