trifluridine

Action and Spectrum

Trifluridine is a nucleoside analog that exerts its anti-cancer effects by incorporating into DNA during replication. Once converted to its active form, trifluridine triphosphate, it replaces thymidine in the DNA strand, causing structural abnormalities and interrupting normal DNA function. This leads to DNA damage and inhibition of cell proliferation. When used in combination with tipiracil, a thymidine phosphorylase inhibitor, trifluridine’s degradation is prevented, thereby increasing its systemic availability and enhancing its cytotoxic activity against cancer cells. 

Drug Interaction

Adverse Reaction

Frequency defined:  

1% to 10% 

Stinging of eyes (5%) 

Burning sensation in eyes  

Frequency not defined: 

Local ocular hypersensitivity reaction 

Dry eye syndrome 

Superficial punctate keratitis 

Black Box Warning

Trifluridine in combination with tipiracil carries a boxed warning for the following: 

Embryo-Fetal Toxicity: The combination may cause harm to a developing fetus if administered during pregnancy. Women of reproductive potential should be advised to use effective contraception. 

Severe Hematologic Toxicities: Serious bone marrow suppression can occur, including neutropenia, anemia, and thrombocytopenia. Regular monitoring of blood counts is essential, and dose modifications may be necessary based on the severity of these toxicities. 

Contraindication / Caution

Contraindication 

Hypersensitivity 

Cautions 

Hematologic Toxicity: Monitor complete blood counts prior to and during treatment, especially for neutropenia, anemia, and thrombocytopenia. Dose adjustments or treatment delays may be required. 

Infection Risk: Due to bone marrow suppression, patients may be at increased risk for infections. Promptly evaluate and treat any signs of infection. 

Renal Impairment: Use caution in patients with moderate to severe renal impairment, as drug exposure may increase. Dose adjustments may be necessary. 

Hepatic Impairment: Limited data are available for patients with moderate or severe liver dysfunction. Use with caution and monitor liver function tests. 

Pregnancy / Lactation

Pregnancy consideration: Due to limited systemic absorption, no adverse effects were observed during animal reproduction studies. 

Lactation: No adverse effects observed for lactating females.  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no evidence of risk to the fetus in the first trimester or the later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Trifluridine is an antiviral drug mainly used as an eye drop to treat herpes simplex virus (HSV) keratitis. It is also a component of the oral chemotherapy combination trifluridine/tipiracil, used to manage metastatic colorectal cancer. Its antiviral effect is achieved by blocking viral DNA synthesis through inhibition of the DNA polymerase enzyme. 

Pharmacokinetics 

Absorption:
After oral administration of Lonsurf (trifluridine/tipiracil), at least 57% of trifluridine is absorbed. Peak plasma concentrations (Tmax) are reached around 2 hours post-dose. Repeated dosing increases exposure, with the area under the curve (AUC) approximately tripling and maximum concentration (Cmax) doubling compared to a single dose. A high-fat, high-calorie meal reduces Cmax by about 40% but does not significantly alter AUC. Systemic absorption from ophthalmic use is negligible. 

Distribution
The apparent volume of distribution (Vd/F) after a single oral dose of 35 mg/m² is approximately 21 liters. Trifluridine is highly protein-bound (>96%), primarily to human serum albumin, and this binding is not affected by dose or co-administration with tipiracil. 

Metabolism
Trifluridine is not metabolized by CYP enzymes. Instead, it is mainly broken down by thymidine phosphorylase into an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). Minor metabolites, such as 5-carboxy-2′-deoxyuridine, are present only in trace amounts in plasma and urine. 

Elimination/Excretion
Around 60% of the administered dose is excreted, primarily through urine (55%), mostly as FTY and glucuronide isomers. Less than 3% of the dose is excreted unchanged, and fecal and respiratory elimination are also under 3%.
After oral administration, the elimination half-life is about 1.4 hours, with a steady-state half-life of 2.1 hours. The half-life of the ophthalmic formulation is much shorter, approximately 12 minutes.
The oral clearance (CL/F) of trifluridine after a 35 mg/m² dose is about 10.5 L/hr. 

Pharmacodynamics 

Trifluridine shows antiviral activity against HSV-1, HSV-2, and vaccinia virus, with some effectiveness against adenovirus strains causing keratoconjunctivitis. It remains effective in herpetic keratitis cases resistant to idoxuridine or vidarabine. In oncology, trifluridine combined with tipiracil exhibits antitumor effects in both 5-FU-sensitive and resistant colorectal cancer models, linked to its DNA incorporation. It also works in KRAS wild-type and mutant cancers. Clinical trials in metastatic colorectal cancer have shown improved PFS, ORR, and DCR with trifluridine/tipiracil, with minimal impact on QT/QTc intervals. 

Adminstartion

Apply one drop of Trifluridine Ophthalmic Solution to the affected eye every two hours while awake, up to nine times daily, until the corneal ulcer fully re-epithelializes. After healing, continue with one drop every four hours while awake (minimum five drops daily) for an additional seven days. If no improvement is seen after 7 days or healing is incomplete after 14 days, alternative treatment should be considered. Use beyond 21 days is not advised due to the risk of eye toxicity. 

Patient Information Leaflet

Patient information leaflet  

Generic Name: trifluridine 

Pronounced: try-FLOOR-ih-deen 

Why do we use trifluridine?  

Trifluridine is a nucleoside analog used to treat eye infections like keratoconjunctivitis and epithelial keratitis caused by the herpes simplex virus. It is also used in combination chemotherapy for some metastatic gastrointestinal cancers.