Mechanism Of Action
Uridine triacetate is an acetylated pro-drug of uridine. Following oral administration, uridine triacetate
is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation.
Uridine competitively inhibits cell damage and cell death caused by fluorouracil.
Fluorouracil is a cytotoxic antimetabolite that interferes with nucleic acid metabolism in normal and
cancer cells. Cells anabolize fluorouracil to the cytotoxic intermediates 5-fluoro-2'-deoxyuridine-5'-
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP inhibits thymidylate
synthase, blocking thymidine synthesis. Thymidine is required for DNA replication and repair. Uridine
is not found in DNA.
The second source of fluorouracil cytotoxicity is the incorporation of its metabolite, FUTP, into RNA.
This incorporation of FUTP into RNA is proportional to systemic fluorouracil exposure. Excess
circulating uridine derived from VISTOGARD is converted into uridine triphosphate (UTP), which
competes with FUTP for incorporation into RNA.
VISTOGARD delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar
doses of uridine itself. Maximum concentrations of uridine in plasma following oral VISTOGARD are
generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours.
Studies 1 and 2 included an assessment of plasma uridine in a subgroup of patients who were overdosed
with fluorouracil or experiencing early-onset of serious fluorouracil toxicities. Samples were obtained
prior to VISTOGARD treatment and at 1 to 4 hours following the first and final doses of VISTOGARD
given at 10 g (adults) or 6.2 grams/m2 (pediatric) every 6 hours for up to 20 doses. Plasma uridine
concentrations are summarized in Table 3.
Table 3 Plasma Uridine Concentrations (μM) in Studies 1 and 2
||Post First Dose
||Post Final Dose
|N = 49
||N = 49
||N = 40
|N = 27
||N = 26
||N = 24
|*Values shown are mean (standard deviation) for plasma uridine (μM)
Food Effect on Uridine PK
A study in healthy adult subjects receiving a slightly different formulation
of uridine triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the
overall rate and extent of uridine exposure.
Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also
crosses the blood brain barrier.
Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic
pathways present in most tissues.
Drug Interaction Studies
In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of uridine triacetate or
uridine on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme
induction data did not reveal an inducing effect of uridine triacetate or uridine on CYP1A2, CYP2B6, or
In vitro data showed that uridine triacetate was a weak substrate for P-glycoprotein. Uridine triacetate
inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 μM. Due to
the potential for high local (gut) concentrations of the drug after dosing, the interaction of
VISTOGARD with orally administered P-gp substrate drugs cannot be ruled out.
In vivo data in humans are not available.
Pharmacokinetics analyses showed that sex did not have a significant effect on uridine
Pharmacokinetic analysis showed that within the age range evaluated (20 to 83 years), age did not have a
significant effect on uridine pharmacokinetics.
Pharmacokinetic analyses showed no clinically meaningful effect of body surface area on uridine PK in
Animal Toxicology And/Or Pharmacology
In mice given a sub-lethal dose of fluorouracil, the administration of oral uridine triacetate diminished
hematological toxicity as a function of increasing dose, but did not completely prevent hematological
toxicity. In mice given a lethal dose of fluorouracil, administration of oral uridine triacetate increased
survival to 90% when given within 24 hours. Survival diminished with increasing interval between the
fluorouracil dose and uridine triacetate treatment demonstrating that earlier administration of uridine
triacetate is more beneficial. In similar experiments in mice, uridine triacetate treatment diminished
damage to the intestinal mucosa caused by fluorouracil treatment.
The efficacy of VISTOGARD was assessed in 135 patients who were treated in two open-label trials,
Study 1 (n=60) and Study 2 (n=75). The patients in both studies had either received an overdose of
fluorouracil or capecitabine, or presented with severe or life-threatening toxicities within 96 hours
following the end of fluorouracil or capecitabine administration. Overdose was defined as
administration of fluorouracil at a dose, or infusion rate, greater than the intended dose or maximum
tolerated dose for the patient's intended regimen of fluorouracil. VISTOGARD was administered at 10
grams orally every 6 hours for 20 doses or at a body surface area adjusted dosage of 6.2
grams/m2 /dose for 20 doses for four patients between 1 and 7 years of age. The major efficacy
outcome was survival at 30 days or until the resumption of chemotherapy if prior to 30 days.
In Study 1 and Study 2 combined, the median age of the patients was 59 years (range: 1 to 83), 56% were
male, 72% were white, 9% were Black/African American, 6% were Hispanic, 4% were Asian, and 95%
had a cancer diagnosis. Of the 135 patients, 117 were treated with VISTOGARD following an overdose
of fluorouracil (n=112) or capecitabine (n=5), and 18 were treated after exhibiting severe or lifethreatening
fluorouracil toxicities within 96 hours following the end of fluorouracil administration.
The severe or life-threatening toxicities involved the central nervous system (such as encephalopathy,
acute mental status change), cardiovascular system, gastrointestinal system (such as mucositis), and bone
marrow. A total of six pediatric patients were administered VISTOGARD. Four patients initiated
VISTOGARD more than 96 hours following the end of fluorouracil or capecitabine administration. Of
the 112 patients overdosed with fluorouracil, 105 (94%) were overdosed by infusion rate only (range
1.3 to 720 times the planned infusion rate), four (4%) were overdosed by dose only, and three (3%)
were overdosed by both dose and rate.
The survival results are shown in Table 4. Of the 135 patients who were treated with VISTOGARD in
Studies 1 and 2 there were five deaths due to fluorouracil or capecitabine toxicity (4%). Of the five
patients who died, two were treated after 96 hours following the end of fluorouracil administration. In
the patients treated with VISTOGARD for an overdose of fluorouracil or capecitabine in Studies 1 and
2 combined (n=117), survival at 30 days was 97% (n=114). In the patients receiving VISTOGARD for
early-onset severe or life-threatening toxicity in Studies 1 and 2 combined (n=18), the survival at 30
days was 89% (n=16). In these studies 33% of patients (n=45) resumed chemotherapy in less than 30
days. Based on retrospective historical case reports of 25 patients who were overdosed with
fluorouracil and received supportive care only, all were overdosed by rate with a range 1.9 to 64 times
the planned infusion rate, and 84% died.
Table 4 Combined Efficacy: All Patients in Study 1 and Study 2
|*Survival includes patients who survived at 30 days or patients who resumed chemotherapy prior to 30