Vistonuridine: A Life-saving Antidote for 5FU Overdose
Approximately 275,000 patients are treated with 5-fluorouracil (5-FU) annually, which is often administered via an infusion pump at or close to its maximum tolerated dose (MTD). When the MTD is exceeded, serious or life-threatening toxicity can result; this often occurs secondary to infusion pump malfunction or programming errors, dose calculation errors, excess or accidental ingestion of oral 5-FU sources (eg, capecitabine or tegafur), or concomitant use of drugs that impair 5-FU degradation. Yet, even patients who receive standard MTD doses can be overexposed when there are deficits in 5-FU degradation enzymes, such as dihydropyrimidine dehydrogenase. The National Institutes of Health estimate that approximately 3% (8250) of patients develop serious toxic reactions from overexposure to 5-FU, with about 1300 dying each year.
Although uridine nucleotides can dilute intracellular fluorouridine nucleotides derived from 5-FU, reducing their ability to incorporate into RNA and become lethal, these nucleotides are poorly bioavailable. Wellstat Therapeutics has developed vistonuridine, the first viable prodrug of uridine, which is an orally administered agent that delivers approximately 8-fold more uridine as it is converted to uridine in the body than administration of uridine itself. Although vistouridine is still an investigational drug, it can be administered under the emergency-use investigational new drug provisions (IND) of the US Food and Drug Administration (FDA).
Currently, 17 patients have been treated with vistonuridine for 5-FU overexposure. The patients' physicians contacted Wellstat after the overdose was discovered, and once emergency-use INDs were obtained from the FDA, vistonuridine was immediately flown in or sent via courier to the clinic. Patients generally received the antidote within 8 to 96 hours after the overdose. All 17 patients made a full recovery, and most experienced relatively mild toxicity, even though a fatal outcome would have been predicted by the dose and rate of 5-FU administration for at least 13 of them. A severity score that integrated dose and infusion rate was calculated for all patients, which can be used by healthcare workers after an overexposure to determine the expected severity and outcome of a 5-FU dose.
In contrast, data for 13 patients with similar 5-FU overdoses were identified in the literature and were used to provide the time course and outcomes for patients receiving only supportive care. Of these patients, 11 died, as would have been predicted by their severity score. The data in both groups support the use of life-saving vistonuridine in the setting of 5-FU overdose, and Wellstat plans to seek regulatory approval in the United States and Europe.