Investigational antidote shows promise for 5-FU overexposure

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.