Trifluridine: A Comprehensive Monograph on a Dual-Indication Nucleoside Analogue

Executive Summary

This report provides an exhaustive analysis of trifluridine, a fluorinated pyrimidine nucleoside with a unique dual role in modern medicine. Initially developed as an antineoplastic agent and later approved as a topical antiviral for herpetic keratitis (Viroptic), trifluridine has been successfully repurposed for systemic oncology in combination with tipiracil (Lonsurf). The monograph details its chemical properties, bifurcated pharmacology, distinct pharmacokinetic profiles, extensive clinical applications in both ophthalmology and oncology, and disparate safety considerations. Furthermore, it explores the drug's developmental history, current research landscape, and future therapeutic potential, offering a comprehensive resource for clinicians, pharmacologists, and researchers.

1. Introduction: The Bifurcated History of a Fluorinated Pyrimidine

Trifluridine, a pyrimidine 2'-deoxyribonucleoside analogue of thymidine, has followed a remarkable and bifurcated trajectory in pharmacotherapy.[1] The molecule was first synthesized in 1964 by Heidelberger and colleagues, originally with antineoplastic intent.[3] However, early clinical investigations of intravenous trifluridine for cancer proved disappointing. The drug exhibited an exceptionally short serum half-life of approximately 12 minutes, which resulted in limited and transient therapeutic responses, halting its initial development as a systemic anticancer agent.[3]

Despite this initial setback, trifluridine found its first clinical success in a different therapeutic area. Its potent antiviral properties led to its development as a topical ophthalmic solution. In 1980, it received approval from the U.S. Food and Drug Administration (FDA) under the brand name Viroptic for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by the herpes simplex virus (HSV).[5] For decades, this remained its primary clinical identity.

The story of trifluridine in oncology was revitalized by a critical scientific breakthrough in understanding its metabolism. Researchers determined that its rapid degradation and poor oral bioavailability were due to extensive first-pass metabolism by the enzyme thymidine phosphorylase (TPase).[3] This understanding led to a rational drug design strategy: combining trifluridine with tipiracil, a potent TPase inhibitor.[3] This combination, known as TAS-102 and later branded as Lonsurf, represented a "pharmacokinetic rescue" of the molecule. By preventing its degradation, tipiracil dramatically improved trifluridine's systemic exposure, allowing it to reach therapeutic concentrations when administered orally. This successful strategy culminated in the FDA approval of Lonsurf in 2015 for patients with metastatic colorectal cancer (mCRC), marking a full-circle return to its original purpose.[1] Trifluridine's journey exemplifies a powerful principle in drug development, where understanding and overcoming pharmacokinetic barriers can unlock the therapeutic potential of an otherwise ineffective molecule. This report analyzes this single chemical entity through the dual lenses of its distinct therapeutic applications, which are fundamentally defined by formulation and pharmacokinetic modulation.

2. Chemical and Physical Characterization

A comprehensive understanding of trifluridine begins with its fundamental chemical and physical properties, which are foundational to its biological activity.

2.1. Nomenclature and Standard Identifiers

Trifluridine is identified globally through a standardized set of chemical names and registry numbers. Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is 1--5-(trifluoromethyl)pyrimidine-2,4-dione.[1] It is also widely known by several common names, including trifluorothymidine (abbreviated as TFT or FTD) and α,α,α-trifluorothymidine.[5] Its unique Chemical Abstracts Service (CAS) Registry Number is 70-00-8, and its DrugBank Accession Number is DB00432.[1]

2.2. Molecular Structure and Physicochemical Properties

Trifluridine is an organofluorine compound classified as a pyrimidine 2'-deoxyribonucleoside.[1] Its molecular formula is

C10​H11​F3​N2​O5​, and it has a molecular weight of approximately 296.20 g/mol.[5] Physically, it is a white to off-white crystalline solid.[2] Its solubility profile shows that it is freely soluble in methanol and acetone; soluble in water and ethanol; and only slightly to sparingly soluble in less polar solvents like diethyl ether and isopropyl alcohol.[5] The melting point is reported to be in the range of 189–193 °C.[11] For clinical use, the ophthalmic solution requires refrigerated storage at 2–8°C to maintain stability, while the powder form is typically stored at -20°C for research purposes.[10]

The following table provides a consolidated reference for the key chemical identifiers and properties of trifluridine.

Table 1: Key Identifiers and Chemical Properties of Trifluridine

Property	Value	Source(s)
IUPAC Name	1--5-(trifluoromethyl)pyrimidine-2,4-dione	1
Common Synonyms	Trifluorothymidine (TFT, FTD), α,α,α-trifluorothymidine, Viroptic, F3T	2
CAS Number	70-00-8	1
DrugBank ID	DB00432	1
PubChem CID	6256	5
Molecular Formula	C10​H11​F3​N2​O5​	5
Molecular Weight	296.20 g/mol	1
Canonical SMILES	C1C@@HO
InChIKey	VSQQQLOSPVPRAZ-RRKCRQDMSA-N
Physical Appearance	White to off-white crystalline powder/solid
Solubility Profile	Soluble in water, ethanol; freely soluble in methanol, acetone
Melting Point	189–193 °C

3. Comprehensive Pharmacology

The pharmacological profile of trifluridine is unique, with its molecular mechanism of action being leveraged against two distinct pathologies: viral infections and cancer. While the core principle of disrupting DNA synthesis is common to both, the specific interactions and clinical strategies differ significantly.

3.1. Mechanism of Action: A Tale of Two Pathologies

Trifluridine's therapeutic effects are rooted in its structural similarity to the natural nucleoside thymidine, allowing it to act as an antimetabolite.

3.1.1. Antiviral Activity: Disruption of Viral DNA Synthesis

As an antiviral agent, trifluridine functions by subverting the viral replication process. It is a nucleoside analogue of deoxyuridine that, upon entering a cell, is phosphorylated by both host and viral enzymes, notably thymidine kinase, to its active triphosphate form. This activated molecule, trifluridine triphosphate, then competes with the natural substrate, thymidine triphosphate, for incorporation into the elongating viral DNA chain by viral DNA polymerase.

The critical feature of trifluridine is the trifluoromethyl (−CF3​) group at the 5-position of the pyrimidine ring. This bulky, highly electronegative group prevents proper base pairing with adenine in the complementary DNA strand. This structural disruption leads to the synthesis of fragile, defective viral DNA, the production of non-functional viral proteins, an increased rate of mutation, and ultimately, the cessation of viral replication. This mechanism has demonstrated efficacy against Herpes Simplex Virus types 1 and 2 (HSV-1, HSV-2), vacciniavirus, and certain strains of adenovirus.

3.1.2. Antineoplastic Activity: A Dual-Pronged Cytotoxic Assault

In oncology, trifluridine exerts its cytotoxic effects through a dual mechanism that differentiates it from other fluoropyrimidines.

First, and most importantly, is its direct incorporation into DNA. Similar to its antiviral action, trifluridine is transported into cancer cells and phosphorylated to trifluridine triphosphate. This active form is then integrated into the DNA of cancer cells, where it causes significant DNA dysfunction, induces double-strand breaks, and triggers cell death. Nonclinical studies have demonstrated a high correlation between the quantity of trifluridine incorporated into DNA and the observed cytotoxic activity, confirming this as its primary antineoplastic mechanism.

Second, trifluridine monophosphate also functions as a reversible inhibitor of thymidylate synthase (TS). TS is a critical enzyme in the de novo synthesis of pyrimidines, responsible for converting deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), an essential precursor for DNA synthesis. This inhibitory action is analogous to that of 5-fluorouracil (5-FU), a cornerstone of chemotherapy for gastrointestinal cancers.

The dual nature of its mechanism provides a distinct advantage. The primary mechanism of action for 5-FU is TS inhibition, leading to a "thymineless death." A common mechanism of resistance to 5-FU involves the upregulation of the TS enzyme by cancer cells. While trifluridine also inhibits TS, its principal cytotoxicity derives from direct DNA incorporation. This means that even if a cancer cell has developed resistance to 5-FU by overexpressing TS, it can remain vulnerable to the DNA-damaging effects of trifluridine. This differentiated mechanism explains its clinical efficacy in patients with mCRC who have previously been treated with and are refractory to fluoropyrimidine-based chemotherapy, positioning it as a valuable therapeutic option for a chemoresistant population.

3.2. Pharmacodynamics: In Vitro and In Vivo Effects

In pharmacodynamic studies, trifluridine has shown potent activity against HSV-1 and HSV-2 both in vitro and in vivo. While the potential for cross-resistance with other nucleoside analogues like idoxuridine exists, clinical evidence shows that trifluridine remains effective in treating herpetic keratitis in patients who have failed therapy with idoxuridine or vidarabine.

In the context of oncology, the combination of trifluridine/tipiracil has demonstrated significant antitumour activity in nonclinical models of both 5-FU-sensitive and 5-FU-resistant colorectal cancer cell lines. Its efficacy in 5-FU-resistant models underscores its distinct mechanism of action. Furthermore, activity has been observed in xenograft models of both KRAS wild-type and KRAS mutant human colorectal cancer, indicating its utility across different molecular subtypes of the disease.

3.3. The Pivotal Role of Tipiracil in Systemic Therapy

The successful repurposing of trifluridine as a systemic oral anticancer agent is entirely dependent on its combination with tipiracil. When trifluridine is administered orally as a single agent, it is subject to rapid and extensive first-pass metabolism in the gut and liver by the enzyme thymidine phosphorylase (TPase). This enzymatic degradation converts trifluridine into an inactive metabolite, 5-(trifluoromethyl)uracil (FTY), resulting in a very short systemic half-life and negligible therapeutic concentrations.

Tipiracil is a potent and specific inhibitor of TPase. By co-formulating trifluridine with tipiracil in a fixed 1:0.5 molar ratio (the combination known as Lonsurf or TAS-102), the enzymatic degradation of trifluridine is effectively blocked. This inhibition leads to a dramatic increase in the bioavailability of trifluridine, with studies showing that its systemic exposure (as measured by the area under the curve, or AUC) is increased by as much as 37-fold compared to trifluridine administered alone. This pharmacokinetic enhancement allows orally administered trifluridine to achieve and sustain the plasma concentrations required to exert its cytotoxic effects on tumor cells.

4. Pharmacokinetic Profiles: Ophthalmic vs. Systemic Administration

The route of administration and formulation fundamentally dictate the pharmacokinetic (PK) behavior of trifluridine, resulting in two distinct profiles that define its separate clinical applications and safety considerations.

4.1. Ophthalmic Formulation (Viroptic): Localized Action

When administered as a 1% ophthalmic solution, trifluridine is designed for local action with minimal systemic effects.

• Absorption: The drug effectively penetrates the cornea and can be detected in the aqueous humor, the fluid inside the front part of the eye. Its penetration is enhanced approximately two-fold in cases where the corneal epithelium is damaged or absent. Critically, systemic absorption following topical ocular administration is negligible.
• Metabolism and Half-life: In animal models, the major metabolite 5-carboxy-2'-deoxyuridine has been identified on the endothelial side of the cornea, though it is not found in detectable levels within the human aqueous humor. The systemic half-life of trifluridine is extremely short, at approximately 12 minutes, but this is not clinically relevant for the ophthalmic formulation due to the lack of significant systemic exposure.

4.2. Oral Combination Formulation (Lonsurf): Systemic Exposure

In its oral formulation combined with tipiracil, the PK profile of trifluridine is characterized by controlled systemic exposure.

• Absorption: Following oral administration, at least 57% of the trifluridine dose is absorbed from the gastrointestinal tract. Peak plasma concentrations (Tmax) are typically reached approximately 2 hours after ingestion. Taking the drug with a high-fat meal reduces the peak concentration (Cmax) by about 40% but does not significantly alter the total drug exposure (AUC). This has led to the recommendation to administer Lonsurf with food, which may help mitigate toxicities associated with high peak concentrations.
• Distribution: Trifluridine has an apparent volume of distribution (Vd/F) of 21 L and is highly bound (>96%) to plasma proteins, primarily serum albumin.
• Metabolism: Trifluridine is not a substrate for cytochrome P450 (CYP) enzymes, minimizing the risk of many common drug-drug interactions. Its primary route of metabolism is via thymidine phosphorylase to the inactive metabolite FTY, the very pathway inhibited by its partner drug, tipiracil.
• Excretion: The drug and its metabolites are eliminated primarily by the kidneys. Within 24 hours, approximately 55% of an administered dose is excreted in the urine, mainly as FTY and glucuronide isomers. Very little (<3%) of the drug is excreted unchanged.
• Half-life: At steady state, the mean elimination half-life of trifluridine is 2.1 hours.

The stark contrast between these two profiles is summarized in the table below.

Table 2: Comparative Summary of Pharmacokinetic Parameters

5. Clinical Efficacy and Therapeutic Applications

Trifluridine's clinical utility is firmly established in two distinct fields: ophthalmology, as a topical antiviral, and oncology, as a component of a systemic oral chemotherapy agent.

5.1. Trifluridine in Ophthalmology

As an ophthalmic solution, trifluridine (Viroptic) has been a long-standing treatment for viral eye infections.

5.1.1. Treatment of Herpetic Keratitis: Indications and Efficacy

The FDA-approved indication for trifluridine ophthalmic solution is the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV types 1 and 2. Its clinical efficacy is well-documented; a pivotal multicenter clinical trial demonstrated a 95% response rate, defined as complete corneal re-epithelialization within a 14-day treatment period. It has also proven effective in patient populations with more challenging disease, showing a 92% response rate in individuals whose infections were unresponsive or who were intolerant to older antiviral agents like idoxuridine or vidarabine.

5.1.2. Comparative Analysis with Acyclovir and Ganciclovir

In the landscape of topical antivirals for herpetic keratitis, trifluridine's efficacy is comparable to that of acyclovir, with both agents being superior to older drugs such as idoxuridine. Ganciclovir has been shown to be at least as effective as acyclovir. While direct head-to-head clinical trials in humans comparing trifluridine and ganciclovir are limited, animal models have suggested equivalent healing capabilities.

The primary distinction between these agents lies in their safety and tolerability profiles. Trifluridine's mechanism of action is nonselective, as it can be phosphorylated and incorporated into the DNA of both viral and healthy host cells. This lack of selectivity is the basis for its potential for significant ocular surface toxicity, particularly with use exceeding 21 days. In contrast, ganciclovir is a prodrug that is preferentially phosphorylated by viral thymidine kinase, making it more selective for HSV-infected cells. This targeted activation results in a lower potential for toxicity to the corneal epithelium. Consequently, ganciclovir ophthalmic gel is often considered a preferred first-line topical agent by many clinicians due to its more favorable safety profile and less frequent dosing schedule.

5.1.3. Administration, Dosing, and Off-Label Considerations

The standard dosing regimen for trifluridine ophthalmic solution is intensive. It requires the instillation of one drop onto the affected cornea every 2 hours while awake, for a maximum of nine drops per day, until the corneal ulcer has fully re-epithelialized. Following healing, the dosage is reduced to one drop every 4 hours (a minimum of five drops per day) for an additional 7 days to prevent relapse. To mitigate the risk of ocular toxicity, continuous administration should not exceed 21 days.

Beyond its approved indication, trifluridine has important off-label uses. The U.S. Centers for Disease Control and Prevention (CDC) recommends its use for the treatment of ophthalmic infections caused by the smallpox or monkeypox (mpox) viruses. Recent preclinical research supports this, demonstrating that trifluridine is effective in vitro against a broad range of mpox isolates, including strains that are resistant to the antiviral tecovirimat. Trifluridine is also used off-label in veterinary medicine for treating ocular herpesvirus-1 infections in cats and dogs.

5.2. Trifluridine/Tipiracil in Oncology

In combination with tipiracil as Lonsurf, trifluridine has become an important therapeutic option for patients with advanced gastrointestinal cancers.

5.2.1. Management of Metastatic Colorectal Cancer (mCRC)

Lonsurf is FDA-approved for the treatment of adult patients with mCRC who have been previously treated with standard chemotherapies, including a fluoropyrimidine, oxaliplatin, and irinotecan, as well as a vascular endothelial growth factor (VEGF) inhibitor. For patients whose tumors are RAS wild-type, they must have also received an epidermal growth factor receptor (EGFR) inhibitor. This places Lonsurf in the third-line or later setting for refractory disease. It is approved for use either as a single agent or in combination with bevacizumab.

5.2.2. Management of Metastatic Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma

Lonsurf is also approved for adult patients with metastatic gastric or GEJ adenocarcinoma who have been previously treated with at least two prior lines of chemotherapy, which must have included a fluoropyrimidine, a platinum agent, and either a taxane or irinotecan.

5.2.3. Pivotal Clinical Evidence: RECOURSE, TAGS, and SUNLIGHT Trials

The approvals of Lonsurf are supported by robust data from large, randomized phase III clinical trials.

• RECOURSE (mCRC): This global trial randomized 800 patients with refractory mCRC to receive either Lonsurf or placebo. The study met its primary endpoint, demonstrating a statistically significant improvement in median overall survival (OS) from 5.3 months with placebo to 7.1 months with Lonsurf (Hazard Ratio 0.68; p<0.001). A significant benefit in progression-free survival (PFS) was also observed (2.0 vs. 1.7 months; HR 0.48; p<0.001). These results established Lonsurf as a standard of care in this setting.
• TAGS (Gastric Cancer): This trial evaluated Lonsurf in patients with heavily pre-treated metastatic gastric or GEJ cancer. It also met its primary endpoint, with Lonsurf showing a significant improvement in median OS compared to placebo (5.7 months vs. 3.6 months; HR 0.69; p<0.001).
• SUNLIGHT (mCRC): This trial investigated the addition of bevacizumab to Lonsurf in 492 patients with refractory mCRC. The combination therapy demonstrated a substantial and clinically meaningful improvement in efficacy over Lonsurf monotherapy. Median OS was extended to 10.8 months with the combination versus 7.5 months with Lonsurf alone (HR 0.61; p<0.001). Median PFS was also more than doubled, from 2.4 months to 5.6 months (HR 0.44; p<0.001). This trial established the Lonsurf plus bevacizumab combination as a new, preferred standard of care in the third-line mCRC setting.

Table 3: Summary of Pivotal Clinical Trials for Lonsurf (Trifluridine/Tipiracil)

6. Safety, Tolerability, and Risk Management

The safety profiles of trifluridine are dramatically different depending on its formulation and route of administration, reflecting the dichotomy between localized topical therapy and systemic cytotoxic treatment.

6.1. Adverse Effect Profiles: A Comparative Overview

Ophthalmic Formulation (Viroptic): The adverse effects are confined to the eye and are generally mild and transient.

• Common (>1%): The most frequently reported adverse reactions in clinical trials were mild, transient burning or stinging upon instillation (reported in 4.6% of patients) and palpebral edema, or eyelid swelling (2.8%).
• Less Common: Other reported local effects include superficial punctate keratopathy (small erosions on the corneal surface), epithelial keratopathy, stromal edema, keratitis sicca (dry eye), hyperemia (redness), increased intraocular pressure, and hypersensitivity reactions.
• Key Concern: The primary safety concern is the potential for ocular toxicity with prolonged use. Continuous administration beyond 21 days is not recommended due to this risk.

Oral Formulation (Lonsurf): The adverse effects are systemic and characteristic of a cytotoxic chemotherapy agent, with myelosuppression being the dose-limiting toxicity.

• Very Common (≥20%): Hematologic toxicities are extremely common. In clinical trials, patients experienced high rates of anemia (77%), neutropenia (67%), and thrombocytopenia (42%). Other very common non-hematologic side effects include asthenia/fatigue (52%), nausea (48%), decreased appetite, and diarrhea.
• Severe (Grade ≥3): Neutropenia is the most frequent severe (Grade 3 or 4) adverse event, occurring in 38% to 52% of patients depending on the study and whether it was used with bevacizumab. Other common severe events include anemia (17-18%) and thrombocytopenia (4-5%). Febrile neutropenia, a serious complication of low neutrophil counts, occurs in approximately 3-4% of patients.
• Combination with Bevacizumab: The overall safety profile of Lonsurf with bevacizumab is similar to Lonsurf alone, though the incidence of Grade 3-4 neutropenia is somewhat higher (52%).

Table 4: Comparison of Common Adverse Effects by Formulation

6.2. Warnings, Precautions, and Contraindications

Ophthalmic: Trifluridine ophthalmic solution is contraindicated in patients with a known hypersensitivity to the drug or its components. It should only be prescribed following a definitive clinical diagnosis of herpetic keratitis, as it is not effective against bacterial, fungal, or chlamydial infections.

Oral: While no absolute contraindications are listed in the prescribing information, Lonsurf carries several significant warnings and precautions :

• Severe Myelosuppression: Due to the high risk of severe neutropenia, anemia, and thrombocytopenia, complete blood counts must be monitored prior to the start of therapy and on Day 15 of each treatment cycle.
• Embryo-Fetal Toxicity: Lonsurf can cause fetal harm. Females of reproductive potential must be advised of the risk and should use effective contraception during treatment and for at least 6 months after the final dose. Males with female partners of reproductive potential should use condoms during treatment and for at least 3 months after the final dose due to the potential for genotoxicity.
• Use in Specific Populations: A dose reduction is required for patients with severe renal impairment (creatinine clearance of 15 to 29 mL/min). Lonsurf should not be initiated in patients with moderate or severe hepatic impairment. Elderly patients (≥65 years) experience a higher incidence of severe hematologic toxicities and should be monitored closely.

6.3. Management of Key Toxicities

The management of myelosuppression from Lonsurf is protocol-driven. The drug must be withheld for Grade 4 neutropenia (<500/mm³), febrile neutropenia, or platelets <50,000/mm³. Once the patient's blood counts recover to acceptable levels, treatment can be resumed at a reduced dose. The use of granulocyte-colony stimulating factors (G-CSFs) to support neutrophil counts is common, reported in 12% to 29% of patients in clinical trials.

6.4. Drug and Food Interactions

Ophthalmic: Due to negligible systemic absorption, clinically significant systemic drug interactions are not expected. If other topical ophthalmic medications are used concurrently, they should be administered at least 5 to 10 minutes apart to avoid washout.

Oral (Lonsurf):

• Drug Interactions: There are over 200 documented drug interactions, with 49 classified as major, necessitating a thorough medication review for any patient starting therapy. In vitro studies suggest that trifluridine and tipiracil are substrates for various drug transporters (CNT1, ENT1/2 for trifluridine; SLC22A2, SLC47A1 for tipiracil). Therefore, co-administration with drugs that inhibit or induce these transporters could potentially alter plasma concentrations of Lonsurf's components.
• Food Interactions: Food has a notable effect on the pharmacokinetics of Lonsurf. A high-fat meal decreases the Cmax of both trifluridine and tipiracil. To ensure consistent absorption and potentially mitigate toxicity related to peak drug levels, it is recommended that patients take Lonsurf within one hour of completing their morning and evening meals.

7. Future Directions and The Research Frontier

The research trajectory for trifluridine is heavily concentrated on expanding its role in oncology, while its application in ophthalmology remains stable but less of a focus for new development.

7.1. Ongoing Clinical Trials in Oncology: Exploring New Combinations and Settings

The clinical development of trifluridine/tipiracil (Lonsurf) is dynamic, with a large number of active trials exploring its potential beyond its current indications. The research can be categorized into several key trends.

A primary focus is the investigation of Lonsurf in novel combination regimens. Building on the success of the SUNLIGHT trial with bevacizumab, researchers are now evaluating Lonsurf in combination with other standard chemotherapies (e.g., irinotecan, oxaliplatin), targeted therapies (e.g., PARP inhibitors like talazoparib), and immunotherapies (e.g., checkpoint inhibitors like pembrolizumab and nivolumab). This strategy aims to identify synergistic effects and overcome resistance mechanisms, positioning Lonsurf not just as a late-line monotherapy but as a versatile backbone agent for combination strategies.

A second major trend is the effort to move Lonsurf into earlier stages of treatment. While currently approved for refractory disease, trials are assessing its utility in the second-line setting and even as an adjuvant or "pre-emptive" therapy for patients with minimal residual disease (as detected by circulating tumor DNA, or ctDNA) following curative-intent surgery for earlier-stage cancers.

Finally, research is underway to expand its use to new patient populations. A particularly noteworthy phase 2 trial is evaluating Lonsurf as a first-line replacement for standard fluoropyrimidines in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. These patients have a genetic inability to safely metabolize 5-FU or capecitabine, and Lonsurf's different metabolic pathway presents a potentially safer and effective alternative.

7.2. Potential for Novel Antiviral Applications

While oncology research dominates, trifluridine's original identity as a broad-spectrum DNA virus inhibitor holds potential for new applications. Preclinical studies have recently demonstrated its efficacy against the mpox virus, including strains resistant to tecovirimat, the primary antiviral used for this infection. This suggests a potential for repurposing trifluridine ophthalmic solution for emerging viral threats, particularly those with ocular manifestations. However, a review of clinical trial registries indicates a lack of active trials for new ophthalmic indications, likely due to the established efficacy and superior safety profile of alternative agents like ganciclovir for its primary indication of herpetic keratitis.

8. Conclusion and Expert Perspective

The therapeutic journey of trifluridine is a compelling narrative of pharmaceutical science, demonstrating how a deep understanding of pharmacology and pharmacokinetics can transform a molecule's clinical destiny. From its initial failure as a systemic anticancer agent to its establishment as a topical antiviral, and its ultimate successful return to oncology through rational combination design, trifluridine stands as a versatile and enduring therapeutic agent.

Its clinical value is now firmly established in two disparate fields. In ophthalmology, Viroptic remains an effective treatment for herpetic keratitis, offering a reliable option that has been in use for over four decades. However, its clinical utility must be weighed against its potential for ocular surface toxicity and the availability of newer, less toxic alternatives like ganciclovir, which are often preferred for first-line topical therapy.

In oncology, Lonsurf has provided a significant and proven survival benefit for patients with heavily pre-treated, refractory metastatic colorectal and gastric cancers. The addition of bevacizumab has further solidified its role as a standard of care in the third-line setting for mCRC. This therapeutic benefit, however, comes at the cost of significant myelosuppressive toxicity, which requires diligent monitoring, patient education, and proactive management, including dose modifications and the use of supportive care agents like G-CSFs.

Looking forward, the future of trifluridine is overwhelmingly centered on its role in cancer treatment. The extensive and diverse portfolio of ongoing clinical trials suggests a strategic shift from viewing Lonsurf as a last-resort monotherapy to its potential use as a flexible backbone agent in combination regimens across multiple lines of therapy. Its oral route of administration, manageable safety profile, and distinct mechanism of action make it an attractive partner for chemotherapy, targeted agents, and immunotherapy. The exploration of its use in specialized populations, such as those with DPD deficiency, and in earlier disease settings for minimal residual disease, signals a promising expansion of its therapeutic reach, ensuring trifluridine's continued relevance in the evolving landscape of modern medicine.

Works cited

1. Trifluridine | C10H11F3N2O5 | CID 6256 - PubChem, accessed September 17, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Trifluridine
2. Trifluridine | 70-00-8 - ChemicalBook, accessed September 17, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6768812.htm
3. Trifluridine/Tipiracil: Old Drug, New Tricks - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5679033/
4. Trifluridine/tipiracil - Wikipedia, accessed September 17, 2025, https://en.wikipedia.org/wiki/Trifluridine/tipiracil
5. Trifluridine - Wikipedia, accessed September 17, 2025, https://en.wikipedia.org/wiki/Trifluridine
6. 207981Orig1s000 - accessdata.fda.gov, accessed September 17, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ODMemo.pdf
7. Trifluridine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 17, 2025, https://go.drugbank.com/drugs/DB00432
8. Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date - Dove Medical Press, accessed September 17, 2025, https://www.dovepress.com/clinical-evaluation-of-the-safety-and-efficacy-of-trifluridinetipiraci-peer-reviewed-fulltext-article-OTT
9. Lonsurf (tipiracil hydrochloride and trifluridine) FDA Approval History - Drugs.com, accessed September 17, 2025, https://www.drugs.com/history/lonsurf.html
10. Trifluridine (NSC 75520) | Thymidylate Synthase inhibitor | 99.96 ..., accessed September 17, 2025, https://www.selleckchem.com/products/Trifluridine(Viroptic).html
11. Trifluorothymidine 70-00-8 | TCI AMERICA - Tokyo Chemical Industry, accessed September 17, 2025, https://www.tcichemicals.com/US/en/p/T2511
12. Trifluridine USP Reference Standard CAS 70-00-8 Sigma-Aldrich, accessed September 17, 2025, https://www.sigmaaldrich.com/US/en/product/usp/1686309
13. Trifluridine ophthalmic dosing, indications, interactions, adverse effects, and more, accessed September 17, 2025, https://reference.medscape.com/drug/viroptic-trifluridine-ophthalmic-343587
14. Trifluorothymidine (NSC 75520, NSC 529182, TFT, Trifluridine, CAS Number: 70-00-8), accessed September 17, 2025, https://www.caymanchem.com/product/21366/trifluorothymidine
15. PRODUCT MONOGRAPH PrVIROPTIC® Trifluridine Ophthalmic Solution, 1% Topical Antiviral Agent Bausch Health, Canada Inc. Date of, accessed September 17, 2025, https://pdf.hres.ca/dpd_pm/00058271.PDF
16. VIROPTIC® Ophthalmic Solution, 1% Sterile (trifluridine ophthalmic solution) - Pfizer, accessed September 17, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=700
17. How LONSURF® Works | Mechanism of Action, accessed September 17, 2025, https://www.lonsurfhcp.com/mechanism-of-action
18. Viroptic: Package Insert / Prescribing Information - Drugs.com, accessed September 17, 2025, https://www.drugs.com/pro/viroptic.html
19. Viroptic (Trifluridine): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 17, 2025, https://www.rxlist.com/viroptic-drug.htm
20. Lonsurf and Alcohol/Food Interactions - Drugs.com, accessed September 17, 2025, https://www.drugs.com/food-interactions/tipiracil-trifluridine,lonsurf.html
21. Trifluridine (Viroptic): Uses, Side Effects, Dosage & More - GoodRx, accessed September 17, 2025, https://www.goodrx.com/trifluridine/what-is
22. TRIFLURIDINE OPHTHALMIC SOLUTION, 1% - DailyMed, accessed September 17, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=abc1d07f-91ee-4421-bc9b-457d0ed41f4c
23. Antiviral treatment and other therapeutic interventions for herpes ..., accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4443501/
24. A New Drug for an Old Nemesis - Review of Optometry, accessed September 17, 2025, https://www.reviewofoptometry.com/article/a-new-drug-for-an-old-nemesis
25. Treating Severe Viral Infections | Ophthalmology Management, accessed September 17, 2025, https://ophthalmologymanagement.com/issues/2011/april/treating-severe-viral-infections/
26. Acute Herpetic Keratitis: What is the Role for Ganciclovir Ophthalmic Gel? - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3619435/
27. What eye drops can be used to prevent herpes simplex keratitis? - Dr.Oracle AI, accessed September 17, 2025, https://www.droracle.ai/articles/184764/eye-drops-to-prevent-herpes
28. Viroptic Dosage Guide - Drugs.com, accessed September 17, 2025, https://www.drugs.com/dosage/viroptic.html
29. Trifluridine Ophthalmic: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 17, 2025, https://www.rxlist.com/trifluridine_ophthalmic/generic-drug.htm
30. Trifluridine for treatment of mpox infection in drug combinations in ophthalmic cell models, accessed September 17, 2025, https://pubmed.ncbi.nlm.nih.gov/38180134/
31. Trifluridine Ophthalmic - VCA Animal Hospitals, accessed September 17, 2025, https://vcahospitals.com/know-your-pet/trifluridine-ophthalmic
32. Trifluridine and tipiracil (oral route) - Side effects & dosage - Mayo Clinic, accessed September 17, 2025, https://www.mayoclinic.org/drugs-supplements/trifluridine-and-tipiracil-oral-route/description/drg-20155709
33. LONSURF (trifluridine and tipiracil) Label - accessdata.fda.gov, accessed September 17, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207981s009lbl.pdf
34. LONSURF® (trifluridine and tipiracil) tablets | Approved for use in Combination with bevacizumab for the Treatment of Patients with Third Line Metastatic Colorectal Cancer, accessed September 17, 2025, https://www.lonsurf.com/
35. FDA Approves LONSURF® (trifluridine/tipiracil) in Combination With Bevacizumab for Adult Patients With Metastatic Colorectal Cancer (mCRC) - Taiho Oncology, accessed September 17, 2025, https://www.taihooncology.com/us/news/2023-08-02_lonsurf-bev_approval/
36. (PDF) Safety profile of trifluridine/tipiracil monotherapy in clinical practice: results of the German compassionate-use program for patients with metastatic colorectal cancer - ResearchGate, accessed September 17, 2025, https://www.researchgate.net/publication/329007473_Safety_profile_of_trifluridinetipiracil_monotherapy_in_clinical_practice_results_of_the_German_compassionate-use_program_for_patients_with_metastatic_colorectal_cancer
37. Lonsurf (Trifluridine plus Tipiracil): A New Oral Treatment Approved for Patients with Metastatic Colorectal Cancer - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5013844/
38. Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer - PubMed, accessed September 17, 2025, https://pubmed.ncbi.nlm.nih.gov/36455504/
39. Real-world treatment patterns and outcomes with trifluridine/tipiracil monotherapy or in combination with bevacizumab in metastatic colorectal cancer. - ASCO Publications, accessed September 17, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3580
40. FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer, accessed September 17, 2025, https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-trifluridine-and-tipiracil-bevacizumab-previously-treated-metastatic-colorectal-cancer
41. Label: TRIFLURIDINE solution - DailyMed, accessed September 17, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abc1d07f-91ee-4421-bc9b-457d0ed41f4c
42. Safety & Side Effects | LONSURF® (trifluridine and tipiracil) tablets + ..., accessed September 17, 2025, https://www.lonsurf.com/side-effects
43. Safety of trifluridine/tipiracil (FTD/TPI) in elderly patients with metastatic colorectal cancer., accessed September 17, 2025, https://ascopubs.org/doi/10.1200/JCO.2018.36.4_suppl.752
44. LONSURF® 3L Treatment for Metastatic Colorectal Cancer, accessed September 17, 2025, https://www.lonsurfhcp.com/
45. Safety of Trifluridine/Tipiracil in Patients With Dihydropyrimidine Dehydrogenase Deficiency Diagnosed With Metastatic Colorectal or Gastroesophageal Cancer | Clinical Research Trial Listing - CenterWatch, accessed September 17, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06245356/safety-of-trifluridine-tipiracil-in-patients-with-dihydropyrimidine-dehydrogenase-deficiency-diagnosed-with-metastatic-colorectal-or-gastroesophageal-cancer
46. Trifluridine Drops - Ophthalmic - MyHealth Alberta, accessed September 17, 2025, https://myhealth.alberta.ca/Health/medications/Pages/conditions.aspx?hwid=fdb8102
47. trifluridine 1 % eye drops - Kaiser Permanente, accessed September 17, 2025, https://healthy.kaiserpermanente.org/health-wellness/drug-encyclopedia/drug.trifluridine-1-eye-drops.216721
48. Tipiracil/trifluridine Interactions - Drugs.com, accessed September 17, 2025, https://www.drugs.com/drug-interactions/tipiracil-trifluridine.html
49. Lonsurf Interactions Checker - Drugs.com, accessed September 17, 2025, https://www.drugs.com/drug-interactions/tipiracil-trifluridine,lonsurf.html
50. Lonsurf® - Oral Chemotherapy Education Sheets, accessed September 17, 2025, https://oralchemoedsheets.com/index.php/sheet-library/25-available/brand-name/75-lonsurf
51. Clinical Trials Using Trifluridine and Tipiracil Hydrochloride - NCI, accessed September 17, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/trifluridine-and-tipiracil-hydrochloride?pn=1
52. Trifluridine/Tipiracil in Combination with Talazoparib for the Treatment of Patients with Locally Advanced or Metastatic Colorectal or Gastroesophageal Cancer - NCI, accessed September 17, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-05678
53. Trifluridine/Tipiracil Benefits Stage IV CRC With Molecular Residual Disease, accessed September 17, 2025, https://www.targetedonc.com/view/trifluridine-tipiracil-benefits-stage-iv-crc-with-molecular-residual-disease
54. Safety of Trifluridine/tipiracil in patients with dihydropyrimidine dehydrogenase deficiency diagnosed with metastatic colorectal or gastroesophageal cancer | MedPath, accessed September 17, 2025, https://trial.medpath.com/clinical-trial/b6d998548d523ce5/2023-508724-35-00-safety-trifluridine-tipiracil-replacement-fluoropyrimidines
55. Search ClinicalTrials.gov for: All | Card Results, accessed September 17, 2025, https://clinicaltrials.gov/search