Summary
Synopsis
Trifluridine 1 (trifluorothymidine) is an antiviral agent for topical use in the eye, and is structurally related to idoxuridine. In vitro studies have shown that it effectively inhibits the replication of herpes simplex virus type I, which causes primary keratoconjunctivitis and recurrent epithelial keratitis in man. In masked comparative studies, predominantly in patients with dendritic ulcers, trifluridine 1 % solution was effective in over 90% of patients; in such studies it was comparable with vidarabine in treating dendritic ulcers, and was at least as effective as, and in some studies more effective than, idoxuridine. The drug was also effective in treating a small number of patients with geographic ulcers (sometimes associated with the usage of topical corticosteroids), and this could be an important advantage if confirmed in further well-designed studies. However, experience at present is too limited to reliably determine the usual response rate in this difficult therapeutic area. In open studies the drug proved to be particularly useful in treating ulcers previously unresponsive to idoxuridine or vidarabine, and in treating patients intolerant of idoxuridine, with a high success rate and minimal side effects being reported. The role of trifluridine in treating deep stromal disease, uveitis, or adenovirus kerato-conjunctivitis has not been established. The drug is well tolerated and cross-hypersensitivity and cross-toxicity between trifluridine, idoxuridine and vidarabine are rare. Thus, trifluridine is an effective alternative to the drugs available for treating herpetic keratitis, and seems especially useful in ‘difficult’ cases.
Pharmacology
Trifluridine is active in vitro against herpes simplex virus type 1, the 50% inhibitory concentration being comparable with that for idoxuridine and lower than for vidarabine. Although most of a small number of type 2 strains of herpes simplex virus tested were inhibited by trifluridine, their sensitivity relative to type 1 strains has yet to be clarified. Additional data on the in vitro susceptibility of adenovirus are also required, particularly as this virus can also cause keratoconjunctivitis in man.
In in vivo studies a wide range of concentrations of trifluridine (0.01 to 10mg/ml) effectively treated herpetic keratitis in rabbits. Masked (double-blind) dose-response studies indicate trifluridine is more potent (on a weight-for-weight basis) than idoxuridine against the McRae strain of herpes simplex virus type 1 in this animal model. Results in treating deeper eye infections, such as herpetic iritis and established stromal keratitis, with trifluridine solution have been somewhat equivocal. However, 1 % trifluridine drops started the day after intrastromal injection of herpes virus, before the infection was established, suppressed the development of corneal stromal disease.
Although trifluridine was effective in vivo (rabbit eye model) against an idoxuridine-resistant strain of herpes simplex, results from another study suggested cross-resistance could occur between trifluridine and idoxuridine or vidarabine. (Nevertheless, it should be noted that in clinical use trifluridine was usually effective in patients previously unresponsive to idoxuridine or vidarabine.)
The specific mechanism of action of trifluridine against herpes viruses is not known, but the drug has been shown to inhibit some of the enzymes involved in DNA synthesis, and trifluridine is incorporated into DNA.
In addition to its antiviral activity, trifluridine inhibits the growth of various uninfected mammalian cells in culture. While it is difficult to determine a meaningful chemotherapeutic index, because of the wide variation in cytotoxic concentrations (probably resulting from the different methods of assessing cytotoxicity), the drug appears to be non-selective in its action on the host cell and the virus. However, the clinical importance of this in vitro finding is uncertain, as the drug has been well tolerated in most patients during short term use (see below).
The closure of epithelial wounds was not delayed, but transient pathological changes to regenerating epithelium have occurred in rabbit eyes treated with trifluridine.
Pharmacokinetics
In the only published pharmacokinetic study following topical administration in man (4 drops of 1 % solution), trifluridine concentrations of 1 to 15µg/ml were found in the aqueous humour of 4 patients with unhealthy corneal epithelium or stroma, but the drug was not detectable in the aqueous humour of a patient with a relatively healthy cornea. 5-Carboxy-2′-deoxyuridine, the product of hydrolysis found in vitro and in isolated perfused rabbit corneas, was not detected in the aqueous humour of these patients. Further data are needed to more clearly establish the extent of penetration of trifluridine through the cornea, and the extent (if any) of systemic absorption following ocular administration.
Therapeutic Trials
Trifluridine has been studied primarily in masked comparative trials with idoxuridine or vidarabine in patients with herpetic keratitis. Although the presently recommended frequency of administration is 2-hourly initially (maximum of 9 drops/day), many of the patients studied used the drug 5 times daily, usually for 2 or 3 weeks. In controlled studies in which dendritic ulcers predominated, trifluridine 1 % solution was effective in over 90% of patients. Trifluridine was comparable with vidarabine in treating dendritic ulcers, and was at least as effective as, and in some studies more effective than, idoxuridine. In these comparative studies, re-epithelialisation of the cornea usually occurred within an average of 7 days, irrespective of the drug used. Not unexpectedly, there was a tendency for geographic ulcers to be less responsive to treatment than dendritic ulcers, although trifluridine was more effective than vidarabine (more rapid healing and improved overall response rate; 85% healing with trifluridine vs 76% with vidarabine) in 1 small study in patients with geographic ulcers, some of which were associated with the usage of topical steroids). Since this is a difficult therapeutic area, such results are encouraging; confirmation in a larger group of patients will be awaited with interest. In addition to the comparative studies, several open studies conducted in patients unresponsive to idoxuridine or vidarabine, or intolerant of idoxuridine, indicate that trifluridine is useful in such patients (overall success rate of 96 % in 104 infected eyes). Well documented cases of clinical resistance to trifluridine have not been reported to date, although a few ulcers have failed to heal with 14 days’ therapy. The drug has been used successfully in patients previously, or concurrently treated with topical corticosteroids.
Side Effects
Trifluridine 1 % ophthalmic solution is generally well tolerated by most patients. Mild, transient burning or stinging upon instillation (approximately 5%) and palpebral oedema (approximately 3 %) occur most frequently. Other reported ‘side effects’ occurring occasionally include punctate epithelial staining with rose bengal, filamentary keratitis, corneal oedema and allergy. Side effects have very rarely necessitated stopping the drug. Cross-hypersensitivity and cross-toxicity between trifluridine, idoxuridine and vidarabine are not a common problem.
Dosage and Administration
The recommended starting dose of trifluridine 1 % solution is 1 drop on the affected cornea every 2 hours while awake (with a maximum of 9 drops/day) until the cornea has completely re-epithelialised. Following this, 1 drop 4-hourly (with a minimum of 5 drops/day) should be used for 7 days. A course of treatment should not exceed 21 days. If there is no improvement after 7 days, or re-epithelialisation is not complete within 14 days, other forms of therapy should be considered.
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Various sections of the manuscript reviewed by: P.S. Binder, Eye Care of La Jolla, La Jolla, California, USA; T.-W. Chang, Infectious Diseases Service, Tufts University School of Medicine, New England Medical Center Hospital, Boston, Massachusetts, USA; DJ. Coster, Department of Ophthalmology, Flinders Medical Centre, South Australia, Australia; E. De Clercq, Rega Instituut, Katholieke Universiteit Leuven, Leuven, Belgium; C. Heidelberger, University of Southern California Comprehensive Cancer Center, Los Angeles, California, USA; R.A. Hyndiuk, Department of Ophthalmology, The Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.; H.E. Kaufman, Department of Ophthalmology, Louisiana State University Medical Center, New Orleans, Louisiana, USA; J.R. McKinnon, Nelson, New Zealand; J. McGill, Southampton Eye Hospital, Southampton, England; D. Pavan-Langston, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; W. Prusoff, Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA; J. Sugar, Department of Ophthalmology, Eye and Ear Infirmary of the University of Illinois Hospital, Chicago, Illinois, USA; TJ. Zimmerman, Department of Ophthalmology, Louisiana State University Medical Center, New Orleans, Louisiana, USA.
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Carmine, A.A., Brogden, R.N., Heel, R.C. et al. Trifluridine: A Review of its Antiviral Activity and Therapeutic Use in the Topical Treatment of Viral Eye Infections. Drugs 23, 329–353 (1982). https://doi.org/10.2165/00003495-198223050-00001
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DOI: https://doi.org/10.2165/00003495-198223050-00001