Trifluridin

Pooled analyses of preregistration clinical trials reported that serum enzyme elevations occurred in up to 24% of patients on trifluridine/tipiracil therapy, but were also elevated in 27% of controls. Similarly, ALT values above 5 times ULN occurred in 2% of trifluridine/tipiracil treated compared to 4% of placebo treated subjects. In these and subsequent studies, clinically apparent liver adverse reactions attributed to trifluridine/tipiracil were not reported.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that trifluridine is expected to have very high mobility in soil(SRC). The pKa of trifluridine is 7.95(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of trifluridine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.5X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Trifluridine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.5X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that trifluridine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant for the neutral species of 9.5X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of -0.46(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trifluridine, which has an estimated vapor pressure of 2.5X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase trifluridine may be removed from the air by wet and dry deposition(SRC). Trifluridine absorbs UV light at wavelengths of 260 nm(4) and, therefore, could susceptible to direct photolysis by sunlight(SRC).

It is unlikely that trifluridine is distributed into milk following topical application to the eye because of the relatively small dosage used, dilution in body fluids, and the short half-life of the drug (approximately 12 minutes). However, the drug should not be used in nursing women unless the potential benefits justify the possible risks to the infant.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of trifluridine can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that trifluridine is expected to have very high mobility in soil. The pKa of trifluridine is 7.95(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ The literature has been reviewed for contact dermatitis from topical antiviral drugs. 15 agents have been identified including acyclovir, imiquimod, podophyllin, podofilox, cidofovir, penciclovir, vidarabine, idoxuridine, trifluridine, tromantadine, lamivudine, interferon intralesional injections and ophthalmic solution, fomivirsen and foscarnet intravitreal injections and ganciclovir intraocular implants. Patch testing has been documented in certain individuals and cross-sensitization has been observed to contribute significantly to some allergic reactions.

/SIGNS AND SYMPTOMS/ Acute overdosage by accidental oral ingestion of trifluridine has not occurred. However, should such ingestion occur, the 75 mg dosage of trifluridine in a 7.5 mL bottle of Trifluridine Ophthalmic Solution is not likely to produce adverse effects. Single intravenous doses of 1.5 to 30 mg/kg/day in children and adults with neoplastic disease produce reversible bone marrow depression as the only potentially serious toxic effect and only after three to five courses of therapy.

/CASE REPORTS/ Prolonged topical trifluridine treatment of herpes simplex keratitis in three elderly patients produced slightly raised dysplastic corneal epithelial lesions. The involved epithelium had a ground-glass appearance and exhibited opaque cells, edema, and spindle-shaped surface cells. Histopathology demonstrated severe cellular atypism, loss of cell polarity, dyskeratosis, parakeratosis, and a few mitotic figures. The pathological change was apparently intraepithelial. After scraping, the edema and opaque cells in the regenerated epithelium gradually disappeared in 3-4 months on cessation of trifluridine therapy. In one patient recurrence of dendritic keratitis, 5 weeks after scraping, was treated by topical bromovinyldeoxyuridine eye drops. Since severe epithelial dysplasia may represent a precancerous condition, prolonged use of trifluridine should be avoided.

/ALTERNATIVE and IN VITRO TESTS/ To study the effects of antiviral agents on human keratocytes in vitro. Cultured human keratocytes were incubated with either ganciclovir, idoxuridine, trifluridine, or cidofovir at concentrations from 0.0001 to 10 mg/mL. Phase-contrast microscopy and XTT (sodium [2,3-bis [2-methoxy-4-nitro-5-sulphophenyl]-2h-tetrazolium-5-carboxanilide, inner salt) colorimetric assay were performed after 24, 48, and 72 hours of incubation. When adjustments were made for time of incubation and concentration, trifluridine reduced cell viability significantly more than ganciclovir, idoxuridine, and cidofovir (p<0.001, three-way analysis of variance). There was significant time-and dose-dependent reduction of cell viability (p<0.001) with trifluridine and cidofovir. After a 72-hour incubation with ganciclovir or idoxuridine, cell viability was reduced as compared with 24- and 48-hour incubation (p<0.001); only the effects of the highest concentration tested (1.0 mg/mL) were significantly different from those of the lower concentrations (p<0.002). At a concentration of 1.0 mg/mL, trifluridine and cidofovir produced moderate to severe signs of cytotoxicity, whereas ganciclovir and idoxuridine displayed much less severe morphologic signs. /These/ results indicate that antiviral agents may have both time- and concentration-related toxic effects on stromal keratocytes. These findings may impact the selection of the most appropriate antiviral drug when it is needed to treat infections involving the corneal stroma.

An estimated BCF of 3 was calculated in fish for trifluridine(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

A pKa of 7.95(1) indicates trifluridine will exist partially in the anion form at pH values of 5 to 9 and, therefore, volatilization of the anion form from water surfaces is not expected to be an important fate process(SRC). The Henry's Law constant for the neutral species of trifluridine is estimated as 9.5X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that trifluridine is expected to be essentially nonvolatile from water and moist soil surfaces(3). Trifluridine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.5X10-13 mm Hg(SRC), determined from a fragment constant method(4).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Corneal wound healing studies in rabbits showed that trifluridine did not significantly retard closure of epithelial wounds. However, mild toxic changes such as intracellular edema of the basal cell layer, mild thinning of the overlying epithelium and reduced strength of stromal wounds were observed.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Whereas instillation of trifluridine into rabbit eyes during a subchronic toxicity study produced some degree of corneal epithelial thinning, a 12-month chronic toxicity study in rabbits in which trifluridine was instilled into eyes in intermittent, multiple, full-therapy courses showed no drug-related changes in the cornea.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Lifetime carcinogenicity bioassays in rats and mice given daily subcutaneous doses of trifluridine have been performed. Rats tested at 1.5, 7.5, and 15 mg/kg/day had increased incidences of adenocarcinomas of the intestinal tract and mammary glands, hemangiosarcomas of the spleen and liver, carcinosarcomas of the prostate gland and granulosathecal cell tumors of the ovary. Mice were tested at 1, 5 and 10 mg/kg/day; those given 10mg/kg/day trifluridine had significantly increased incidences of adenocarcinomas of the intestinal tract and uterus. Those given 10 mg/kg/day also had a significantly increased incidence of testicular atrophy as compared to vehicle control mice.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a non-standard test, trifluridine solution has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs.

For more Non-Human Toxicity Excerpts (Complete) data for Trifluridine (9 total), please visit the HSDB record page.

Trifluridine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Trifluridine absorbs light at wavelengths of 260 nm(2) and, therefore, could be susceptible to direct photolysis by sunlight(SRC).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 82 workers (14 of these were female) were potentially exposed to trifluridine in the US(1). Occupational exposure to trifluridine may occur through inhalation and dermal contact with this compound at workplaces where trifluridine is produced or used. Exposure to trifluridine among the general population may be limited to those administered the drug(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including trifluridine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Synthesis: prepared by treatment of 5-trifluoromethyluracil with a bacterial enzyme.

Preparation ... C. Heidelberger, United States of America 3201387 (1965 to US Dept HEW)

Trifluridine Ophthalmic Solution, 1% in a 7.5 mL fill packaged in a natural plastic bottle with a natural plastic flat tip and a white plastic closure.

Trifluridine sterile ophthalmic solution contains 1% trifluridine in an aqueous solution with acetic acid and sodium acetate (buffers), sodium chloride, and thimerosal 0.001% (added as a preservative).

Trifluridine, a fluorinated pyrimidine nucleoside, is structurally related to idoxuridine (no longer commercially available in the US) and thymidine. Trifluridine differs structurally from thymidine in the presence of 3 fluorine atoms in place of 3 hydrogen atoms in the methyl group of the latter compound.