Vistonuridine: An Orally Administered, Life-Saving Antidote For 5-Fluorouracil (5fu) Overdose

9616 Background: 5FU is widely used to treat solid tumors and is often administered via infusion pump at or near its maximum tolerated dose (MTD). Toxicities and even death can occur in patients over-exposed to 5FU. Uridine is a direct biochemical antagonist of 5FU toxicity; uridine nucleotides dilute intracellular fluorouridine nucleotides derived from 5FU, reducing their lethal incorporation into RNA. However, uridine is poorly bioavailable (7%) and is therefore not a clinically viable antidote. Vistonuridine is an orally administered prodrug of uridine that delivers approximately 8-fold more uridine than administration of uridine itself. Methods: 17 patients overdosed with 5FU have been treated with vistonuridine as an antidote. Patients received vistonuridine (10g q6h for 20 doses) beginning 8 to 96 hours after overdose. Data from 13 patients with similar 5FU overdoses provide the time course and outcomes for patients receiving available supportive care without vistonuridine. A severity score, integrating dose and infusion rate, was calculated for all the patients, and this tool could be used by healthcare workers to determine the expected severity and outcome of a 5FU overdose. Results: All 17 overdose patients treated with vistonuridine recovered fully. Most, especially those for whom vistonuridine treatment was initiated sooner, had relatively modest toxicity. In marked contrast, all 11 of the literature-reported cases of 5FU overdose for which an outcome of death would have been predicted died from the overdose despite receiving available supportive care. Conclusions: These clinical data illustrate the serious, debilitating and life threatening nature of 5FU overdose and the current lack of effective treatments. Vistonuridine appears to be a safe and effective, life-saving antidote to 5FU overdose. [Table: see text]