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Drug Evaluations

Drugs 23: 329-353 (1982)


0012-6667/82/0500-0329/$12.50/0
© ADIS Press Australasia Pty Ltd. All rights reserved.

Trifluridine: A Review of its Antiviral Activity


and Therapeutic Use in the Topical Treatment
of Viral Eye Infections

AA. Carmine, R.N. Brogden, R.C. Heel, T.M. Speight and


G.s.Avery
Australasian Drug Information Services, Auckland

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; 0..1. Coster, Department of
Ophthalmology, Ainders Medical Centre, South Australia, Australia; E. De Clercq, Raga Instituut,
Katholieke Universiteit Leuven, Leuven, Belgium; C. Heidelberger, University of Southern Califor-
nia Comprehensive Cancer Center, Los Angeles, California, USA; RA. Hyndiuk, Department of
Ophthalmology, The Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.; H.E. Kauf-
man, Department of Ophthalmology, Louisiana State University Medical Center, New Orleans,
Louisiana, USA; JR. 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; T..1. Zimmer-
man, Department of Ophthalmology, Louisiana State University Medical Center, New Orleans,
Louisiana, USA.

Contents

Summary ........................................................................................................................................ 330


I. Pharmacology ............................................................................................................................ 332
1.1 Antiviral Activity In Vitro .................................................................................................. 332
1.1.1 Herpes Simplex Virus Type I .................................................................................. 332
I. 1.2 Herpes Simplex Virus Type 2 .................................................................................. 333
1.1.3 Vaccinia Virus .......................................................................................................... 333
1.1.4 Adenovirus ................................................................................................................ 335
1.2 Antiviral Activity in Rabbit Eyes ...................................................................................... 335
1.2.1 Herpetic Keratitis ...................................................................................................... 335
1.2.2 Vaccinial Keratitis ...................................................................................................... 336
1.2.3 Deeper Ocular Infections .......................................................................................... 336
Trifluridine: A Review 330

1.3 Mechanism of Action ...................................... ................................................. 337


1.4 Toxicology........................................... .......................... ........................ 338
1.4.1 Cytotoxicity and Viral Specificity ............................................................................. 338
1.4.2 Adverse Effects on Rabbit Eyes ....... ........................................ 340
1.4.3 Mutagenicity and Oncogenicity 340
1.4.4 Dysmorphogenicity ................ . 340
2. Pharmacokinetics. 341
2.1 Intraocular Penetration 341
2.2 Metabolism .............. . 341
3. Therapeutic Trials ...................................................................................................................... 342
3. I Herpetic Keratitis ...................................................... . ....................................................... . 344
3.1.1 Comparisons with Idoxuridine .................... ................ .................. ............ ................ 344
3.1.2 Comparisons with Vidarabine .................................................................................. 344
3.1.3 Recurrent Herpetic Keratitis .................................... ................ .................................. 344
3.1.4 Other Difficult Situations .......................................................................................... 347
3. I . 5 Clinical Resistance .................. .......... .......... ................ .............................. ............ .... 348
3.2 Adenovirus Keratoconjunctivitis ............................................................................. 348
4. Side Effects .................................................................................................................. 348
5. The Place of Trifluridine in Treating Ophthalmic Viral Infections ........ ............ ........................ 349
6. Dosage and Administration ....................................................................................................... . 350

Summary Synopsis: Trijluridine' (trijluorothymidine) 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 J, which causes primary keratoconjunctivitis and
recurrent epithelial keratitis in man. In masked comparative studies, predominantly in patients
with dendritic ulcers, trijluridine I % 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 deter-
mine 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 trijluridine 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 trijluridine, idoxuridine and vidarabine
are rare. Thus, trijluridine 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 I, 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 I 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.

'Viroptic' (Burroughs Wellcome).


Trifluridine: A Review 331

In in vivo studies a wide range of concentrations of trifluridine (0.0 I to I Omg/ mJ) effec-
tively treated herpetic keratitis in rabbits. Masked (double-blind) dose-response studies indi-
cate trifluridine is more potent (on a weight-for-weight basis) than idoxuridine against the
McRae strain of herpes simplex virus type I in this animal model. Results in treating deeper
eye infections, such as herpetic iritis and established stromal keratitis, with trifluridine solu-
tion 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-resis-
tant strain of herpes simplex, results from another study suggested cross-resistance could oc-
cur between trifluridine and idoxuridine or vidarabine. (Nevertheless, it should be noted that
in clinical use trifluridine was usually effective in patients previously unresponsive to idox-
uridine 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 un-
certain, 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 ad-


ministration in man (4 drops of I % solution), trifluridine concentrations of I to 15j.1g/ 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 ad-
ministration.

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 con-
trolled studies in which dendritic ulcers predominated, trifluridine I % 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 I 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 idox-
uridine, 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
Trifluridine: A Review 332

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 cortico-
steroids.

Side Effects: Trifluridine I % 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' oc-
curring 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 oftrifluridine I % solution is


I 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, I 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.

1. Pharmacology aI., 1968). Thus, in vitro findings should be in-


terpreted with care.
Trifluridine or trifluorothymidine [5-trifluoro-
methyl- 2' -deoxyuridine, 2' -deoxy- 5-(trifluoromethyI) 1.1.1 Herpes Simplex Virus Type 1
uridine] is a fluorinated pyrimidine nucleoside, and is n
Several studies (table have shown that at con-
a structural analogue of the deoxyribonucleoside, centrations of about 0.2 to 1.7~g/ml trifluridine in-
thymidine, and of the established antiviral agent, hibits the cytopathic effects of herpes simplex type I
idoxuridine (see Heidelberger et al., 1962, 1964; and by 50 % , as measured by the plaque reduction assay
fig. I). or the reduction in viral-induced cytopathogenicity in
various cell cultures (Collins and Bauer, I 977a,b,
1979; De Clercqet aI., 1978b, 1979, 1980; Schaeffer
1.1 Antiviral Activity In Vitro et al., 1978; Torrence et aI., 1977). Plaque formation
was reduced 98.5 % when herpes simplex type I
As with many other types of drugs, in vitro studies cultured in Vero cells was treated with 17 ~g/ ml
of an antiviral agent may give an indication of its po- (50~moI) of trifluridine (Lin et al., 1976).
tential usage in vivo, but they do not necessarily pre- In most studies comparing the in vitro activity of
dict its efficacy and safety in animals and humans (De trifluridine against herpes simplex type I with that of
Clercq et ai., 1980; Lennette and Eiferman; 1978; the established antiviral agents idoxuridine and
Marks, 1974). A number of factors can affect the vidarabine, trifluridine and idoxuridine have
determination of the antiviral activity of a compound generally tended to be of comparable potency, and
in vitro, including the particular strain of virus tested considerably more active on a weight-for-weight
(De Clercq et ai., 1980), the cell culture system basis than vidarabine (Collins and Bauer, I 977a,b,
(McSwiggan et ai., 1975), the assay method (Collins 1979; De Clercq et ai., 1978b, 1979; Prusoffet ai.,
and Bauer, I 977a) and the type of media (Hyndiuk et 1977; Schaeffer et al., 1978; Torrence et al., 1977).
Trifluridine: A Review 333

However, in a more recent study in which the sen- 1979) was very wide, with 2 strains being insensitive
sitivity of I I strains (of clinical and laboratory origin) at the maximum non-toxic concentration (27)lg/ml
of herpes simplex type I were tested, idoxuridine ap- or 80)lmoi). In contrast, there was comparatively lit-
peared to be the more active compound in that the tle variation in the sensitivity of the 7 strains oftype 2
average 50 % inhibitory concentration was herpes simplex tested by De Clercq et al. (1980).
0.13)lg/ml, compared with 0.7)lg/ml oftrifluridine Thus, further data are required to clarify the relative
(De Clercq et aI., 1980). Furthermore, both in this susceptibility of type 2 strains of herpes simplex virus
study and in another in which 5 viral strains were to trifluridine in vitro.
tested (Collins and Bauer, 1977a,b, 1979), the range
of idoxuridine concentrations required to inhibit ail 1.1.3 Vaccinia Virus
the strains tested was narrower than that of Trifluridine inhibited the replication of vaccinia
trifluridine (see table I for quantitative data). virus in various cell cultures. The 50 % inhibitory
concentration was between O. I and 0.2)lg/ ml (0.3 to
1.1.2 Herpes Simplex Virus Type 2 0.6)lmoJ) in human HeLa and primary rabbit kidney
Whereas type I herpes simplex virus primarily in- cells (De Clercq et aI., 1978b, 1980; Parkhurst et aI.,
fects non-genital sites such as the eyes, lips, mouth, 1976; Torrence et aI., 1977) and O.4)lg/ml (I.3)lmoO
skin, brain and spinal cord, type 2 strains are pri- in human skin fibroblasts (Torrence et aI., 1977). The
marily of urogenital origin (Nahmias and Roizman, greatest inhibitory effect of the drug on the formation
1973). Type 2 strains seem to be less sensitive to of infectious vaccinia virions occurred when it was
idoxuridine than type 1 strains (table I), while the sen- added to HeLa cells between I hour before and 2
sitivity to trifluridine of the smail number of type 1 hours after the virus (Parkhurst et aI., 1976).
and 2 strains tested so far tends to overlap (Collins Trifluridine appears to be 2 to 3 times more active
and Bauer, 1977a,b, 1979; De Clercq et aI., 1980). against vaccinia virus than against herpes simplex
However, the variation in the susceptibility of the 5 virus type I cultured in primary rabbit kidney cells,
type 2 strains tested by Collins and Bauer (1977a,b, unlike idoxuridine which is as active, or more active,

o o 0
II
HN~CF3 11 CH3 :)11 I
HN :) I HN I
O~~.') N ~~N O~~N
HOCH 2 0 HOCH 2 0 HOCH 2 0

HO HO HO

T rifluridine Thymidine Idoxuridine

Fig. 1. Structural formulae of trifluridine, thymidine and idoxuridine.


Table I. In vitro activity of trifluridine, idoxuridine and vidarabine against herpes simplex virus type 1 (HSV-l) and type 2 (HSV-2)

Author Cell Viral assay Virus Results in fJg/ml (fJmol)2 -I


~
culture' method (strain) c
trifluridine idoxuridine vidarabine 5:

~

Torrence et al. HSF Cytopathogenicity HSV-l ID50= 0.44 0.16 13 l>


:xl
(1977) L . .)3 (1.3) (0.57) (37)
'(ii'"
<
PRK Cytopathogenicity HSV-l ID50 = 0.22 0.16 5
::E
L . .)3 (0.66) (0.57) (15)

De Clercq et al. HSF Cytopathogenicity HSV-l (KOS) ID50= 0.2 0.1


(1977) PRK Cytopathogenicity HSV-l (KOS) ID50 = 0.4 0.4 4

De Clercq et al. PRK Cytopathogenicity HSV-l (KOS) ID50= 0.2 0.2 4


(1978b, 1979)

De Clercq et al. PRK Cytopathogenicity HSV-l ID50 = 0.7 0.13 7


(1980) (multiple strains) range = 0.4-1.0 0.1-0.15 2-15
PRK Cytopathogenicity HSV-2 ID50= 0.7 0.3 5
(multiple strains) range = 0.3-1.0 0.2-0.4 2-10

Collins and Bauer Vero Plaque reduction HSV-l ED50 = 0.25-1.7 0.11-0.26 1.6-9.0
(1977a,b, 1979) (multiple strains) (0.75-4.9)4 (0.39-0.91 )" (4.6-25.7)4

Vero Plaque reduction HSV-2 ED50 = 0.29- > 27 0.25-1.3 4.4-22.1


(multiple strains) (0.87 - > 80)4.5 (0.87-4.57)4 (12.6-63.1 )4

Schaeffer et al. Vero Plaque reduction HSV-l ID506 = 0.5 0.3 5.6
(1978) (lCI) (1.5) (1 ) (16)

Lin et al. Vero Plaque formation HSV-l 1.5 x 105pfu 7 with


(1976) (Cl-l0l) 17fJg/ml (5OfJmol)

Prusoff et al. Vero HSV-l 98.6 % inhibition with 99.5% inhibition with
(1977) L . .)3 17fJg/mi (5OfJmol) 14fJg/mi (5OfJmol)

1 HSF = human skin fibroblasts; PRK = primary rabbit kidney; Vero = cells from the green monkey kidney.
2 If results were quoted in fJmoles these values are provided in brackets. From these the concentrations in fJgI ml were calculated.
ID50 = concentration inhibiting viral-induced cytopathogenicity by 50%.
3 1 strain, but type not specified.
4 ED50 ranges were calculated from a figure and in some cases confirmed by a table and the text. ED50 was not defined, but was derived from dose-response
graphs.
5 Trifluridine was inactive against 2 strains, hence the upper limit could not be obtained.
6 Not defined, but calculated from dose-response lines.
7 There were 1.5 x 105 plaque forming units in trifluridine-treated cultures compared with 100 x 105 plaque-forming units in untreated cultures. w
w
8 Not specified. ~
Trifluridine: A Review 335

against herpes simplex type I as against vaccinia (De In this animal model, trifluridine was more potent
Clercq et al., 1978b, 1980). on a weight-for-weight basis than idoxuridine against
the McRae strain of herpes simplex virus type I
1.1.4 Adenovirus (Kaufman, 1965; Hyndiuk and Kaufman, 1967); the
The activity of trifluridine against adenovirus is of concentration of trifluridine resulting in a 50 %
interest since various types of this virus can cause response (EDso) was 0.08mg/ml for the 9th passage
keratoconjunctivitis (Editorial, 1977), including types of this strain (Kaufman, 1965) and 0.3mg/ ml for the
8 and 19 which have been isolated in epidemics of 11th passage (Hyndiuk and Kaufman, 1967), while
this disease (Guyer et al., 1975). To date there is only for idoxuridine it was about 0.7mg/ml in both cases.
I published report on the in vitro activity of Although trifluridine I Omg / ml and idoxuridine
trifluridine against adenovirus (Lennette and Eifer- 1.0mg/ ml given 5 times daily for 4 days were signifi-
man, 1978). In this study, trifluridine at a concentra- cantly (p <0.0 j) more effective than saline in reduc-
tion of 50 to 70)Jg/ ml inhibited the replication of 4 ing the severity of dendritic ulcers in rabbit eyes, bet-
strains of adenovirus, with serotypes 13 (2 strains) ter results were obtained with both drugs when these
and 19 being inhibited to a much greater extent than doses were given 12 times daily (Hyndiuk and Kauf-
serotype 8. man, 1967). These authors also found trifluridine
was more effective than idoxuridine in reducing the
viral titre in rabbit corneas infected with herpes
1.2 Antiviral Activity in Rabbit Eyes simplex. In fact, there was no assayable virus on days
2 and 4 of the 7 days of treatment with trifluridine,
Rabbit eyes have become accepted as an appropri- but the virus was present in idoxuridine-treated eyes
ate model in which to test herpetic keratitis (Glasgow, throughout this period. However, within 2 days of
1976), although the predictive value of the results stopping both drugs the viral content had increased to
may well depend on the manner in which the disease above the levels in the control animals; it then
is assessed. A recommended approach involves grad- decreased to nil in all groups (including the controls)
ing corneal ulcers in rabbits on a 0 to 4 scale in which by day 14. With a longer course (14 days) of idox-
o represents no ulcers and 4 represents ulcers cover- uridine treatment, the virus was not detectable by day
ing the entire cornea, and making assessments by 9 and there was no such increase in viral content on
'masking' the scorer (Kaufman, 1976, 1978). This discontinuing treatment.
approach has been used in most of the studies Although trifluridine is usually administered to
reported below. patients as a I % solution, ointments of trifluridine
(3 %) and idoxuridine (0.5 %) were similarly effective
1.2.1 Herpetic Keratitis in healing corneal ulcers (graded on a 0 to 4 scale),
In dose-response studies in rabbits with herpetic and both drugs were significantly better than placebo
keratitis, trifluridine 0.01 to 10mg/ml reduced the (Kaufman et al., 1978). In another masked study also
severity of corneal ulcers, when compared with a using ointments (but a different system for grading
saline control under masked conditions (Kaufman, the ulceration), 0.5 % idoxuridine appeared to heal
1965; Kaufman and Heidelberger, 1964; Hyndiuk ulcers in rabbit eyes faster than I % trifluridine and
and Kaufman, 1967). Similarly, in other studies 3 % vidarabine. Nevertheless, all 3 drugs were consi-
(Bauer et ai., 1979; Collins and Bauer, I 977b; Kauf- derably more effective than placebo (Bauer et ai.,
man et al., 1978), trifluridine I and 3 % ointments 1979).
and 0.5 % solution applied 5 times daily for 4 or 5 Trifluridine was also active in vivo against a strain
days were effective in treating type I herpetic of herpes virus which was resistant to idoxuridine,
keratitis. with the same EDso (O.08mg/mO as an idoxuridine-
Trifluridine: A Review 336

sensitive strain (Kaufman, 1965). However, in pears to have reasonable intraocular penetration (see
another study investigating the cross-resistance be- section 2.1), its efficacy in treating deeper herpetic in-
tween antiviral agents in vivo (Gauri, 1979), fections is of special interest.
trifluridine was inactive against a strain of herpes Keratouveitis (inflammation of the cornea, iris,
simplex virus which had been propagated in the pre- ciliary body and choroid) was induced in rabbits by
sence of idoxuridine, thereby inducing resistance to inoculating unscarified eyes with herpes simplex
idoxuridine. Also, in the same study both idoxuridine virus type I. After 4 days without treatment, during
and vidarabine were inactive against a trifluridine- which active epithelial keratitis developed, both I %
resistant strain of herpes simplex virus type I, but a trifluridine drops given 6 times daily for 6 days, and
strain of herpes simplex virus type 2 with induced- 0.1 % idoxuridine drops given 8 times daily, signifi-
resistance to trifluridine was sensitive to vidarabine. cantly decreased epithelial ulceration, and as a result
Hence, it appears that in certain circumstances there the mean scores for conjunctivitis and iritis were also
can be cross-resistance between trifluridine and idox- reduced. Trifluridine differed significantly from idox-
uridine or vidarabine. The clinical implications of uridine in that post-treatment viral cultures were
these findings are uncertain, but it should be noted negative in all 9 eyes treated with trifluridine but in
that trifluridine has often been useful in a small num- only 4 of 9 receiving idoxuridine (Pavan- Langston et
ber of patients previously unresponsive to idoxuridine aI., 1979). Only mild iritis and conjunctivitis were ob-
or vidarabine (see section 3.1.4). served in the above study (and probably simply
reflected the severity of epithelial disease), but in other
1.2.2 Vaccinial Keratitis studies (Maudgal et al., 1982; Sugar et al., 1973) her-
In man this condition, for which there is no petic iritis was specifically induced by injecting herpes
established treatment, may occur as a serious but rare simplex virus into the anterior chamber of rabbit
complication of smallpox vaccination (Hyndiuk et al., eyes. Treatment was started the following day. The
1976). Trifluridine O.lmg/ml eyedrops (Kaufman severity of iritis remained relatively constant during 8
and Heidelberger, 1964) or 0.5 and 5% ointments days' treatment with 1% trifluridine drops 9 times
(Hyndiuk et aI., 1976) were more effective than daily (Maudgal et aI., 1982). After 4 days' treatment
placebo in reducing the severity of ulcers resulting with a high concentration (5 %) of trifluridine ad-
from a vaccinia virus infection in rabbit eyes. After ministered frequently (I2 times/day), the degree of
treating vaccinial keratitis in rabbits for 6.5 days, iritis was mild, while moderate iritis occurred in
0.5 % trifluridine ointment applied 5 times daily had untreated eyes (Sugar et al., 1973).
'cleared' the lesions, and reduced the number of posi- Trifluridine I % drops 6 (McNeill and Kaufman,
tive viral cultures, to a much greater extent than 1979) or 9 times daily (Maudgal et al., 1982) sup-
0.5 % idoxuridine. Although 5 % trifluridine oint- pressed the development of corneal stromal disease
ment completely cured the disease in this animal when started I day after intrastromal injection of
model, 2 of the 10 eyes treated with this high con- herpes simplex virus into rabbit eyes. However, when
centration of the drug developed fine, discrete punc- treatment was started 7 days after viral inoculation,
tate corneal opacities. These cleared within 3 days of Maudgal et al. (I 982) found trifluridine again
stopping treatment (Hyndiuk et al., 1976). markedly decreased the extent of deep stromal
keratitis compared with a placebo, but McNeill and
1.2.3 Deeper Ocular Injections Kaufman (I 979) found the course of the disease was
Deeper herpetic infections are more difficult to unaffected by treatment. These conflicting results
treat than epithelial keratitis, mainly because of the could be due to a number of factors [see Maudgal et
difficulty of getting adequate amounts of drug to the al. (I 982) for discussion]. Whether the maintenance
disease site (Sugar et al., 1973). Since trifluridine ap- of stromal disease is predominantly affected by im-
Trifluridine: A Review 337

mune mechanisms or virus multiplication is not en- 1.3 Mechanism of Action


tirely clear, but this is an interesting area for further
study. Although the specific mechanism of action by
Once daily subconjunctival injections of which trifluridine inhibits the production of herpes
trifluridine 2.5mg were ineffective in treating stromal virus in cells is unknown, its antiviral activity proba-
keratitis, irrespective of when treatment was initiated bly results from the various effects of the drug on the
(McNeill and Kaufman, 1979). synthesis of DNA, and from its incorporation into

2 -Deoxyuridine -monophosphate

1 ,"ymidy.oo 'ym"'''~'
Thymidine -----i.~Thymidine-monophosphate
thymidine
kinase'

l,"ymidYI'" ",,"

Thymidine-diphosphate

1"""."". dipho",h". ",,"

Thymidine-triphosphate

1 DNA polym.",,'

DNA"

1 Trifluridine is a competitive inhibitor with respect to thymidine for thymidine kinase. This enzyme catalyses the phos-
phorylation to trifluridine monophosphate.
2 Trifluridine monophosphate irreversibly inhibits thymidylate synthetase.
3 Trifluridine triphosphate is a competitive inhibitor with respect to thymidine triphosphate for cell- and virus-induced
DNA polymerases.
4 Trifluridine triphosphate is incorporated into cell and vaccinia virus DNA.

Fig. 2. Metabolic pathway leading to the incorporation of thymidine into DNA, and showing the steps at which trifluridine ap-
parently exerts an influence.
Trifluridine: A Review 338

DNA. This area of investigation has been reviewed in varying results with regard to cytotoxicity (table II).
detail by Heidelberger and King (J 979). Most studies determined total cell counts in the pre-
Trifluridine (a thymidine analogue) acts at several sence and absence of the drug and found that
stages in the biosynthetic pathway leading from 2- trifluridine 0.01 to 17~g/ml (3 x 10- 2 to 50~moJ)
deoxyuridine-5' monophosphate to the formation of inhibited the growth of various uninfected mam-
DNA (fig. 2). Trifluridine is a competitive inhibitor malian cells (containing thymidine kinase) in culture
with respect to thymidine for thymidine kinase (Cheng et ai., 1975; Lin et ai., 1976; Parkhurst et al.,
(Bresnick and Williams, 1967; Wigdahl and 1976; Prusoffet al., 1977; Umeda and Heidelberger,
Parkhurst, 1978). The drug is phosphorylated by 1968). Since it appears that the enzyme thymidine
thymidine kinase to trifluridine monophosphate kinase is required for trifluridine to exert its cytotoxic
(Bresnick and Williams, 1967), which in turn in- effect (Parkhurst et aI., 1976; Wigdahl and
hibits thymidylate synthetase (De Clercq et ai., Parkhurst, 1981), much higher concentrations of the
1978a; Reyes and Heidelberger, 1965). After further drug are required to inhibit the growth of cells which
phosphorylation to trifluridine triphosphate, this lack this enzyme (for example NSF and BF cells;
compound competitively inhibits the incorporation of table II).
thymidine triphosphate into DNA and is incorporated In order to alter the normal morphology of prim-
instead (Tone and Heidelberger, 1973). The incor- ary rabbit kidney cells, a concentration of 40~g / ml
poration of trifluridine into DNA has been demon- was required (De Clercq et al., 1980), although in the
strated with vaccinia virus (Fujiwara and Heidel- same study as little as 0.01 ~g/ml inhibited (by 50 %)
berger, 1970), bacteriophage T4 (Gottschling and the incorporation of deoxyuridine into host cell DNA.
Heidelberger, 1963) and mammalian cells (Fujiwara Trifluridine and its nucleotide also produced an ir-
et aI., 1970). reversible cytotoxic effect on HeLa cell colony forma-
Incorporation oftrifluridine into DNA of vaccinia tion, which is thought to result from the incorpora-
virus cultured in HeLa cells resulted in the production tion of the drug (as trifluridine triphosphate) into
of morphologically defective, non-infectious virions, cellular DNA (Parkhurst et aI., 1976). Other studies
and faulty transcription of late messenger RNA (Dex- (Fujiwara et al., 1970; Umeda and Heidelberger,
ter et aI., 1973; Fujiwara and Heidelberger, 1970; 1968) also suggest that trifluridine is incorporated
Oki and Heidelberger, 197 J). It has been suggested into cellular DNA.
that this would result in formation of abnorm'al In those studies which related drug concentrations
virion proteins (Heidelberger and King, 1979). causing cytotoxicity with those resulting in antiviral
Although such an effect has not yet been clearly activity (Cheng et al., 1975; De Clercq et aI., 1978b,
shown with herpes simplex virus, the evidence avail- 1979, 1980; Lin et al., 1976; Parkhurst et al., 1976;
able so far suggests that the mechanism of action Prusoff et al., 1977; Umeda and Heidelberger, 1968),
of trifluridine against herpes viruses is the same thereby giving an indication of the chemotherapeutic
as against vaccinia virus (Heidelberger and King, specificity of trifluridine, results are again somewhat
1979). variable (see table II). While some studies found that
antiviraI activity occurred at a lower concentration
than that which inhibited cell growth (De Clercq et
1.4 Toxicology aI., 1978b; Umeda and Heidelberger, 1969), others
showed that a particular concentration of trifluridine
1.4.1 Cytotoxicity and Viral Specificity had similar inhibitory effects on viraI mUltiplication
Several parameters and celllines have been used to and mammalian cell growth (Cheng et al., 1975; Lin
determine the cytotoxic effects of trifluridine, and et aI., 1976; Parkhurst et al., 1976; Prusoff et aI.,
these differing approaches have produced widely 1977). Furthermore, other studies (De Clercq et al.,
Trifluridine: A Review 339

Table II. Effect of the specified concentration of trifluridine on various uninfected cells. and on herpes simplex virus type 1
(HSV -1) or vaccinia virus

Author Cell Incubation T rifluridine


culture' period (days)
concentration inhibition of inhibition
Ilg/ml (mol) cell growth (%) of virus

Prusoff et al. (1977) Vero 3 17 100 HSV-l


see also (SOx 10- 6 ) 98.6%
Cheng et al. (1975) Vero 3 0.3 67
and Lin et al. (1 x 10- 6 )
(1976)

Parkhurst et al. He La 3 0.1 50 Vaccinia


(1976) (3x 10. 7 ) 50%
NS 3 0.03 50
(1 x 10- 7 )
NSF 3 675 50
(2x 10- 3 )
L5178Y 3 0.01 50
(3 x 10- 8 )

Umeda and He La 3 0.3 50


Heidelberger (1968) (10- 6 )
NSF 3 3376 50
(10- 2 )
L5178Y 3 0.02 50
(5x 10- 8 )
BF 3 16880 50
(5x 10- 2 )

De Clercq et al. PRK 3 30 HSV-l


(1978b) 50% at 0.2Ilg/ml
Vaccinia
50% at O.lllg/ml

De Clercq et al. PRK 0.05 HSV-1


(1979) 50% at 0.2Ilg/ml

De Clercq et al. PRK <11 0.01 HSV-l


(1980) 50% at 0.7Ilg/ml
PRK 3-4 40 Vaccinia
50% at 0.2Ilg/ml

1 Vero =cells from the green monkey kidney; HeLa = human cells; NS = Novikoff hepatoma cells; NSF = Novikoff hepatoma
cells lacking thymidine kinase; L5178Y = mouse leukemic lymphoblast cells; BF = mouse leukemic lymphoblast cells lacking
thymidine kinase; PRK = primary rabbit kidney cells.
2 No t stated.
3 16 hours.
4 Concentration which inhibited (by 50 % ) the incorporation of (2 - '''C)2' -deoxyuridine into the DNA of normal uninfected PRK
cells.
5 Concentration which caused a microscopically visible disruption of normal cell morphology in about 50% of the cells.
Trifluridine: A Review 340

1979, 1980) suggest that trifluridine is 'negatively test systems (data on file, Burroughs Wellcome). In
selective', in that it inhibits host-cell DNA synthesis the sister chromatid exchange test, which is a sensi-
at concentrations well below those that inhibit viral tive indicator of chromosomal damage, trifluridine
replication. Nevertheless, when used clinically, the increased the exchange rate in human lymphocytes
drug has been well tolerated by most patients (see sec- and fibroblasts, particularly at high concentrations
tion 4). (5pg/ml) [Cassiman et al., 1981]. Trifluridine was
Because of the wide variation in these results, a shown to be mutagenic to bacteriophage T4B, as a
meaningful chemotherapeutic (or selectivity) index result of its incorporation into DNA (Gottschling and
cannot be calculated for trifluridine. Heidelberger, 1963). Although the drug was
mutagenic to synchronous Chinese hamster ovary
1.4.2 Adverse Effects on Rabbit Eyes cells (Aebersold, 1979), this was not the case in a
There was no evidence of corneal toxicity (assessed similar study by Huberman and Heidelberger (t 972).
by biomicroscopic examination, and staining) when However, their Chinese hamster cells were not syn-
normal rabbit eyes were treated with a high con- chronised. The significance of these results is not
centration of trifluridine (5mg/ml 12 times per 24 clear, but the possibility exists that mutagenic agents
hours) for a week (Hyndiuk and Kaufman, 1967). may cause genetic damage in humans.
However, in rabbits with standardised corneal The oncogenic potential of trifluridine is
epithelial defects, 8 days' treatment with trifluridine unknown, but is currently being evaluated in rodents.
(t % drops 8 times daily) or idoxuridine (0.1 % drops A published study (Jones et al., 1976) has shown that
8 times daily) caused pathological changes to the neither trifluridine nor idoxuridine produced on-
regenerating epithelium, which quickly reversed on cogenic transformation of mouse embryo cells,
stopping therapy (Foster and Pavan-Langston, 1977). although the structurally similar compound 5-
The rate of closure of these epithelial wounds was not fluoro- 2' -deoxyuridine did so.
significantly retarded by either drug.
However, stromal wound healing appears to be 1.4.4 Dysmorphogenicity
affected by trifluridine in that tensile strength was sig- A study in pregnant rabbits showed that 2 drops
nificantly reduced (compared with a control) 12 days of 1 % trifluridine applied topically 4 times a day on
after wounding, during which time 3 drops of the days 6 to 18 of pregnancy was not dysmorphogenic,
1 % solution were administered 4 times daily, but not but that 0.1 % idoxuridine given in the same dosage
after the same dosage regimen of 0.1 % idoxuridine schedule did produce fetal abnormalities (Itoi et al.,
(Gasset and Katzin, 1975). When wound strength 1975). The preservative, thiomersal, used in the com-
was measured by other methods (the pressure re- mercial formulation of trifluridine solution, also had
quired to rupture the wound and hydroxyproline no dysmorphogenic effects when high doses were
levels), stromal wounds treated with trifluridine 1 % given topically to rabbits or systemically to rats
drops 8 times daily for 3 weeks tended to be weaker (Gasset et al., 1975).
than saline-treated controls, but the differences were Trifluridine was not dysmorphogenic when up to
not statistically significant. ldoxuridine-treated eyes 5mg/kg/day was administered subcutaneously to
did have significantly weaker wounds as determined rats and rabbits, although bone formation was
by hydroxyproline levels (Foster and Pavan- delayed when a dosage of 2.5mg/kg/day was given
Langston, 1977). (data on file, Burroughs Wellcome). When
trifluridine was injected into the yolk sac of develop-
1.4.3 Mutagenicity and Oncogenicity ing chicken embryos, high mortality and dys-
Trifluridine has exerted mutagenic, DNA damag- morphogenic effects occurred (Kury and Crosby,
ing and cell transforming activities in various in vitro 1967).
Trifluridine: A Review 341

2. Pharmacokinetics trifluridine within 30 minutes of corneal transplanta-


tion (Pavan-Langston and Nelson, 1979). Results
2.1 Intraocular Penetration from both studies suggest trifluridine adequately
penetrates the unhealthy cornea. I to I 5J.lg I ml (3 to
Trifluridine, like idoxuridine and vidarabine, 44J.1moI) of the drug entered the aqueous humour in
penetrates the cornea by non-facilitated diffusion, as those patients with unhealthy epithelium or stromal
shown by its linear kinetics of penetration through thinning, although no drug was found in a patient
excised, perfused, rabbit corneas and lack of satura- with healthy intact epithelium and scarred normal
tion kinetics (O'Brien and Edelhauser, 1977). How- thickness stroma. 5-Carboxy-2'-deoxyuridine was not
ever, when all 3 drugs are present at the same con- detected in any patient's aqueous humour (minimum
centration (25J.1mol = about 8J.1g1 mI), trifluridine detectable levels of the drug and its hydrolysate were
penetrates rabbit corneas faster than idoxuridine or 2J.1moI). Further data are required to establish the ex-
vidarabine, both in the presence 04.2, 11.6 and tent of intraocular penetration in patients with
2.6pmol/min/cm 2 of each drug, respectively) and ab- healthy and unhealthy corneas.
sence (28.5, 25.7 and 13.4pmol/minl cm 2, respec- When normal healthy adults (number of subjects
tively) of the epithelium. Although distribution of not stated) used trifluridine I % eye drops 7 times
trifluridine and its hydrolysate are similar in the pre- daily for 14 days, neither trifluridine nor 5-car-
sence or absence of rabbit corneal epithelium (fig. 3), boxy- 2' -deoxyuridine were detectable in serum (data
the rate of penetration is doubled when the epithelium on file, Burroughs Wellcome).
is removed (O'Brien and Edelhauser, 1977).
Intraocular penetration was also determined by
measuring the amount of drug in the aqueous 2.2 Metabolism
humour of infected and uninfected rabbit eyes (fig. 4,
Sugar et aI., 1973), and in 5 patients with a history of Trifluridine is unstable in bicarbonate-Ringer's
herpetic keratitis who received 4 drops of I % solution at pH 7.6 and 34°C, with 18 to 25 % of the

(A) (8)

Trifluridine Trifluridine Trifluridine Trifluridine


hydrolysate hydrolysate

Epithelial 75% 21% 70% 29%


side
reservoir

Stroma 7/ / / / / ////1
Endothelial 78% 19% 71% 25%
side
reservoir

Fig. 3. The relative distribution of radioactive trifluridine and its hydrolysate. 5-carboxy-2' -deoxyuridine. in the presence (A)
and absence (B) of the epithelium. This experiment. in isolated perfused rabbit comeas. was initiated by adding radioactive
trifluridine to the media on the epithelial side of the corneas. After 3 hours the radioactive compounds in each of the reservoirs
was analysed. The percentage of the total radioactivity recovered and identified is shown (after O'Brien and Edelhauser. 1977).
Trifluridine: A Review 342

drug being hydrolysed over 3 hours (O'Brien and usually in the form of dendritic ulcers, and this condi-
Edelhauser, 1977). 5-Carboxy- 2' -deoxyuridine was tion was diagnosed by its characteristic appearance.
the only breakdown product detected in this and Although geographic (amoeboid) ulcers represent a
another in vitro study (Clough et al., 1978), and also different herpetic disease which is less amenable to
when tritiated trifluridine was studied in isolated per- therapy, in some studies a few of these cases have
fused rabbit corneas (O'Brien and Edelhauser, 1977). been analysed together with the dendritic lesions, and
In the latter study this hydrolysate, which has little or this can distort the results.
no activity against herpes simplex virus according to In the following studies 'healing' was nearly al-
Clough et al. (J 978), and trifluridine were present in ways defined as the absence of corneal staining with
similar proportions on either side of the corneal fluorescein or rose bengal. However, a treatment
epithelium (fig. 3). It appears that the hydrolysis of failure not only occurred when the cornea did not
trifluridine is dependent on pH and ionic strength completely re-epithelialise within a specified period
(Clough et aI., 1978; O'Brien and Edelhauser, 1977). (usually 14 days), but also when a lesion did not
decrease in size during the first 7 days of treatment,
or it enlarged over several consecutive visits. For this
3. Therapeutic Trials reason the results below and in the tables are pre-
sented in terms of failure rates, generally defmed as
Trifluridine has been studied in several masked above unless otherwise specified. In most studies
comparative trials with idoxuridine or vidarabine patients were followed for about 7 days after stopping
(adenine arabinoside), and in a few open trials. The the drug to determine the incidence of recur-
majority of patients studied had herpetic keratitis, rentlrecrudescent ulceration and other complications.

40

~
:::J
co 0
Q E 30
f;.!::::J
-

co <f)
:::J
Q)
0
"o
co Q)
:::J
"cr
co 20
.~o
~E
~'01
~2- 10

t t t 30 60
Time (minutes)

Fig. 4. Concentrations of trifluridine detected in the aqueous humour of 10 rabbit eyes scarified and infected with herpes
simplex virus 3 days previously (--), and in 6 eyes not scarified or infected (---). 4 drops !indicated by arrows) of the 1 % solu-
tion were given over 15 minutes (after Sugar et aI., 1973).
Table III. Masked studies comparing trifluridine (T) and idoxuridine (I) drops in patients with herpetic keratitis
::;i
Initial :::;;
Author Type of Duration Dosage in Prior or Symptoms Results
C
:::l.
keratitis of drops/day concomitant pretreatment size of e.
(no. of treatment (no. of (days) lesion complications

steroids failed days ~
patients) (days) patients) (no. of (mm 2 ) to to (% of T patients :l>
patients) heal heal vs % of I :0
CD
patients) <
% iii'
:E
Laibson et al. Dendritic 14 T' 4.3 0 5.8 Superficial
(1977) (30) (16) stromal disease
Geographic I' 3.2 24 3 6.1 (19% vs 18%)
(3) (17) Disciform keratitis
(0 vs 0)

Pava n-Langston Dendritic 14 1% Tx9 3 6.7 4 5.5 Recurrence


and Foster (34) (23) (0 vs 0)
(1977) Geographic 0.1% Ix 19 7.2 37' 5.3
(5) (16)

Wellings et al. Dendritic or 14 1% Tx5 4 3.2 8 6.3 Disciform keratitis


(1972) geographic (40) (3% vs 3%)
(78) 0.1% Ix 5 4 1.6 40 5 8.2
(38)

Sugar et al. Dendritic 14 1% Tx9 8 8.5 5.7 86 6.4


(1980) (44) (26)
0.1% Ix 19 3 6.7 4.2 17" 8.1
(18)
Geographic 14 1% Tx9 2 62 12 25 6 6.0
(17) (8)
0.1% Ix 19 5 36 17 66 6 6.7
(9)

Not clearly stated.


2 'Same' for both groups, no sizes given.
3 Includes 1 patient (6 %) with unspecified' drug toxicity'.
4 Includes 2 patients (12 %) who were drug or regimen intolerant.
5 Note relatively low dosage of idoxuridine used, compared with that presently recommended.
6 Failure simply defined as an unhealed lesion after 14 days' treatment or a recurrence within 7 days post-treatment.
7 If there were any recurrences with either drug they are included as failures. W
-I>
W
Trifluridine: A Review 344

3,1 Herpetic Keratitis with I % trifluridine solution healed in an average of


5,8 days, while only 2 % of ulcers treated with
3,1,1 Comparisons with 1doxuridine vidarabine failed to heal in 14 days, Not unexpec-
In 4 studies, 2 of which were multicentred (Sugar tedly, geographic ulcers proved rather slower and
et ai" 1980; Wellings et ai" 1972), I % trifluridine harder to heal (fig,S), Of particular interest, it was in
solution was compared in a masked fashion with such cases that the only statistically significant differ-
0,1 % idoxuridine solution in treating herpetic ence between trifluridine and vidarabine occurred,
keratitis (table III), When dendritic ulcers predomi- when 15 % of geographic ulcers treated with
nated, less than 9 % failed to heal with trifluridine trifluridine and 24 % treated with vidarabine failed to
(5 or 9 drops/day for 14 days), However, the failure heal (Coster et aI., 1979), About half of all patients in
rate was somewhat higher in a small group of this study were already using topical steroids; these
patients with geographic ulcers, some of whom were were gradually reduced and stopped during the study,
using topical corticosteroids concomitantly (Sugar et Since this is a difficult therapeutic area, such results
aI., 1980), In all studies there were fewer failures are encouraging, If they are confirmed in a larger
with trifluridine than with idoxuridine, although the group of patients, trifluridine will offer improved
difference in failure rates between the drugs was therapy of this condition,
statistically significant (p <0,05) in only 2 studies In a study (Coster et aI., 1976) in which reduced
(Pavan-Langston and Foster, 1977; Wellings et aI., dosages (3 drops / day) of I % trifluridine and 3,3 %
1972), I of which (Wellings et aI., 1972) used vidarabine were given for only 3 days after re-
dosages lower than those currently recommended, epithelialisation (and not 5 times daily for 7 days as
Unpublished results from all of the idoxuridine-con- currently recommended), there was a relatively high
trolled studies in patients with dendritic ulcers incidence of recrudescence of epithelial herpetic
showed 3 of 81 (4 %) patients treated with trifluridine disease (9 % with trifluridine and 24 % with
and 9 of 58 (J 6 %) treated with idoxuridine failed to vidarabine), Apart from recurrence/ recrudescence,
heal within 14 days (p <0,05), Of the 16 patients the incidence of other complications of viral infection
with geographic ulcers who were treated with was generally similar with both drugs (table IV),
trifluridine, only 2 (J 2 %) failed to heal, While 10 of
17 (59 % ) such patients failed to heal with idoxuridine 3,1.3 Recurrent Herpetic Keratitis
(p <O,OJ) [data on file, Burroughs Wellcome]. Recurrences of herpetic keratitis are a common
The average healing time of around 6 days was feature of the disease; indeed, in I study, within 2
similar for both drugs and both types of ulcer years of their first dendritic ulcer (treated with idox-
(table III), The incidence of disease complications (as uridine) 26 % of 89 patients had another, While over
opposed to side effects) arising during or after treat- this period there was a 43 % recurrence rate in 70
ment was also similar (see table III) when such data patients who had a history of I or more previous at-
were reported, tacks of herpetic keratitis (Carroll et ai" 1967), On
the basis of present knowledge it appears that recur-
3,1.2 Comparisons with Vidarabine rences of herpetic ocular disease may result from
Masked studies (Coster et ai" 1976; Van Bijster- reactivation and shedding of a latent form of herpes
veld and Post, 1980), and a study of unspecified simplex virus which resides in the sensory neurons of
design (Travers and Patterson, 1978), using various the trigeminal ganglion (Nesburn, 1975), While
dosage regimens and forms, have shown trifluridine trifluridine is useful in treating recurrent episodes of
and vidarabine to be similarly effective in healing the disease (see sections 3,1.1, 3,1. 2 and 3,1.4), in
dendritic ulcers (table IV), In a well-executed study view of the above theory it is unlikely that this, or
(Coster et ai" 1976), all 45 dendritic ulcers treated other antiviral drugs, could affect the incidence of
Table IV. Masked studies comparing trifluridine (T) and vidarabine (V) in patients with herpetic keratitis

~
Author Type of Daily dosage No. of Prior or Initial Results :i!
c
keratitis and patients concomitant size of ~
duration ophthalamic lesion failed days complications s·
!'!
drugs (mm 2 ) to to (% of T patients l>
(% of all heal heal vs % of V :JJ
CD
patients) (%) patients) <
C;;.
~

Coster et al. (1976); Dendritic 1 % T drops' 5.1 03 5.8 Recrudescence /


45 )
McKinnon et al. recurrence
(1975) steroids 2 and (9% vs 24%)
1% atropine Disciform keratitis
(9% vs 9.5%)
3.3 % V ointment' 42/ 4.97 23 5.1 Nondisciform keratitis
(7% vs 7%)

Coster et al. Geographic 1 % T drops' steroids 2 15" Recurrence


13 }
(1979) and (0 vs 6%)
3.3% V ointment' 17 1% atropine 24"

Van Bijsterveld Dendritic 2% T ointment6 .7 11" 11.1" Recurrence


28 }
and Post (1980) 0.2% (0 vsO)
3% V ointment' 28 scopolamine 14" 10.5"

1 Given 5 times daily until healed, then 3 times daily for 3 days.
2 If already on steroids these were gradually reduced and withdrawn during the study.
3 Within 14 days.
4 Within 21 or 22 days.
5 Geographic ulcers treated with vidarabine took significantly longer to heal (see fig. 5).
6 Not commercially available.
7 Given 4-hourly while awake until healed, then for another week.
8 More stringent definition of healing than in other studies (includes absence of epithelial oedema and cystic changes). w
.j>.
<11
-I
3;
c
a:
5'
!'!
l>
:II
CD
<
0;'
Dendritic ulcers Geographic ulcers
:E
100

100

75
75-1 n=13

15
soJ
25 II
*-
"0
Q)
roQ)
;::::

5
~
Q)
c.>
50

25

5 10 14 5 10 15 20
Time to heal (days)

Fig. 5. Cumulative frequency graphs of time taken to heal dendritic and geographic ulcers treated with 1 % trifluridine eye drops (0--0) or 3% vidarabine
w
ointment (0 - - 0 ) five times daily (after Coster et aI., 1976, 1979). ~

'"
Trifluridine: A Review 347

recurrences. Indeed, Falcon et al. (I 977) found there placebo- (and steroid-) treated patients in this double-
was no meaningful difference in recurrence rates masked study did develop ulcers (Sundmacher,
(24 % and 23 %, respectively) within 12 months of 1978).
treating 131 patients with trifluridine and 106
patients with idoxuridine for their first simple 3.1.5 Clinical Resistance
dendritic ulcer. A more extensive study by Although there have been a few ulcers which
Wilhelmus et al. (I 980 also found that trifluridine failed to heal with trifluridine (see sections 3.1.1,
did not differ from other treatments with regard to 3.1.2 and 3.1.4), it is unclear whether these are exam-
subsequent recurrence rates. ples of true clinical resistance (as defined by McGill et
al., 1975). From a retrospective survey of patient
3.1.4 Other Difficult Situations records, Falcon et al. (I 977) reported the incidence of
In several open studies (see table V), patients with resistance to treatment as 1 % of 363 patients using
a recent or past history of unresponsiveness/clinical trifluridine, 7 % of 164 patients on vidarabine and
resistance or intolerance (including toxicity or allergy) 14 % of 534 patients on idoxuridine. No details were
to idoxuridine or vidarabine were treated with 5 to 9 given regarding cross-resistance between these 3 anti-
drops/day of 1 % trifluridine for about 14 days. Ofa virals. To date there have been no published reports
total of 83 dendritic and 21 geographic ulcers which of human herpetic keratitis resistant to all 3 drugs.
fell into this 'difficult' category, there were only 4
failures (including 1 atopic patient who developed
severe blepharodermatitis - see section 4 - and 1 3.2 Adenovirus Keratoconjunctivitis
whose ulcer had increased in size by day 11 of
trifluridine treatment). In the absence of characteristic corneal, eyelid or
In addition to those patients in table V, in other facial lesions, the clinical signs and symptoms of
uncontrolled reports McGill et al. (197 4a, 1975) also acute follicular conjunctivitis and keratoconjunctivitis
reported using trifluridine successfully in 7 patients caused by herpex simplex and adenovirus can be simi-
clinically resistant to vidarabine, and in 7 patients lar, hence the correct diagnosis must be made by
with geographic ulcers (treated with steroids initially) cultural or serological tests (Darougar et al., 1978).
which failed to heal with idoxuridine. Although Differential diagnosis of these 2 conditions is impor-
steroids can sometimes prolong and complicate the tant because there has been no established chemo-
treatment of superficial herpetic keratitis (Williams et therapy for adenovirus keratoconjunctivitis
al., 1977), they did not appear to affect healing with (Editorial, 1977; Galasso, 1981).
trifluridine in those patients who had recently used, In a masked placebo-controlled study in which 10
or were still using them (McGill et al., 1974a; volunteers (20 eyes) were infected with adenovirus
McKinnon et al., 1975; Pavan-Langston and Foster, type 3, subsequent treatment with 1 % trifluridine 5
1977; Sugar et al., 1980). times daily for 8 days did not appear to affect the
The clinical use of trifluridine in deep herpetic course of this self-limiting infection (Little et al.,
keratitis is very limited. 6 of 7 cases of deep keratitis 1968). However, when 1 % trifluridine was used
treated in an open study with steroids and 6 clinically during an outbreak of keratoconjunctivitis
doses/ day of trifluridine healed in an average of 14 due to a different serotype of adenovirus (type 19),
days, with a recurrence in 1 case 18 days later (Fran- severe and persistent symptoms in 12 patients were
cois et al., 1979). When 28 patients with steroid-tre- completely cleared within 4 days of a 7-day course
ated keratouveitis were also given prophylactic (Darougar et al., 1977). Well-designed studies are re-
trifluridine 5 times daily for about 7 weeks, there quired to clarify trifluridine's role in treating kerato-
were no cases of dendritic keratitis. However, 6 of 28 conjunctivitis due to various adenovirus serotypes.
Trifluridine: A Review 348

4. Side Effects occasionally reported punctate epithelial staining with


rose bengal (e.g. Coster et al., 1976, 1979) and fila-
The assessment of adverse reactions to topical mentary keratitis, eyelid oedema and allergy in rare
antiviral agents can be complicated by the fact that instances (e.g. Coster et al., 1976; Sugar et al., 1980).
similar effects are sometimes associated with the Stromal oedema, irritation, keratitis sicca, hy-
underlying disease. Nevertheless, trifluridine I % peraemia, and increased intraocular pressure have
ophthalmic solution used up to 9 times daily for up to been associated with the drug very rarely (data on file,
21 days is generally well tolerated. The manufacturer Burroughs Wellcome).
states that the adverse reactions most frequently In a retrospective survey of patient records, Falcon
reported during controlled clinical trials were mild, et al. (I 977) found that the incidence of toxicity with
transient burning or stinging upon instillation (4.6 %) trifluridine (4 %) was the same as for vidarabine and
and palpebral oedema (2.8 %). Published trials have less than for idoxuridine (table VI). The frequency of

Table V. Open studies in which patients unresponsive to, or intolerant of, idoxuridine (I) or vidarabine (V) were treated with
1% trifluridine (T) solution

Author Type of Failed Dosage of Prior or con- Initial Results


keratitis on I T and comitant size of
(no. of and/or V duration steroids lesion failed days
lesions) (no.)' (days) (no. of (mm 2) to to
patients) heal heal
(%)

Hyndiuk et al. Dendritic lor V 2 hrly4 05 6.1


(1978) (14)2 C .. )3 () 14)

Laibson et al. Dendritic 1(12) 5.6 0 6.0


(1977) ( 11) (14)
Geographic
(1)
McGill et al. Dendritic 1(24) 5 times/day 12 0 7.1
(1974a) (17) C .. )3
Geographic
(7)

Pavan-Langston Dendritic 1(13) 2 hrly4 5 5.9 13 6.3


and Foster (13) V (5) « 14)
( 19771 Geographic
(2)

Sugar et al. Dendritic 1(27) 2 hrly4 13 5.4 0 7.0


(1980) (28) V (3) (14)
Geographic 1(10) 2 hrly4 3 8.4 18 11.9
(11 ) V (5) (14)

Some patients were unresponsive to both drugs. hence numbers in this column may not equal those in column to the left.
2 14 episodes in 11 eyes and 10 patients.
3 Not stated.
4 While awake.
5 Recrudescence in 2 cases of ulceration (14 %). which both responded to a second course of trifluridine.
Trifluridine: A Review 349

Table VI. Incidence of toxicity and hypersensitivity with idoxuridine, trifluridine and vidarabine' (after Falcon et aI., 1977)

Drug Nu mber of full Incidence of


courses of treatment
toxicity (%) hypersensitivity (%)

Idoxuridine 534 10 7
Trifluridine 363 4 3
Vidarabine 164 4

1 Based on a retrospective survey of patient records in 1 ophthalmology department.

cutaneous hypersensitivity reactions to trifluridine However, in other reports toxicity was not a problem
(3 % ) was intermediate between the other 2 drugs, No when the drug was given to a few patients for up to 3
details of the nature of these reactions are given, months (McGill et al., 1974b; Sundmacher, 1978).
Discontinuation of trifluridine because of side
effects is very rare. In one such patient, severe
blepharodermatitis occurred within 48 hours of tak- 5. The Place of Trifluridine in Treating
ing the drug. However, this patient was severely Ophthalmic Viral Infections
allergic to almost every cosmetic or drug used, includ-
ing idoxuridine and vidarabine (Pavan-Langston and Trifluridine 1 % solution was effective in over
Foster, 1977). 90 % of patients studied in controlled trials in which
Although serious allergic contact dermatitis with dendritic ulcers predominated, and there were few
idoxuridine and trifluridine was verified in another side effects. It appears to be about as effective as
patient (Cirkel and van Ketel, 1981), cross-hypersen- vidarabine in healing these ulcers, and in some studies
sitivity between these drugs is rare, despite the was superior to idoxuridine. With all 3 drugs, re-
similarity in their structures. In fact, 8 patients who epithelialisation of the cornea usually occurs within
were hypersensitive to idoxuridine, and sometimes to an average of 7 days.
other topical ophthalmics, did not have any such reac- Not unexpectedly, it seems that geographic ulcers
tion during an average of 19 days' treatment with are less amenable to therapy with trifluridine than
trifluridine (MdJill et al., 1974a). dendritic ulcers. However, in a small study in patients
Similarly, in other studies a few patients who had with geographic ulcers (sometimes associated with
previously not tolerated idoxuridine, were suc- steroid usage), trifluridine was more effective than
cessfully treated with trifluridine (Laibson et al., vidarabine; if such results are confirmed in a larger
1977; Pavan-Langston and Foster, 1977; Sugar et al., group of patients, trifluridine will be a welcome addi-
1980), tion to available treatments in this difficult thera-
The manufacturer recommends avoiding mere peutic area.
than 21 consecutive days of treatment with Whether topically administered trifluridine is ap-
trifluridine because of unspecified potential ocular propriate for the treatment of herpetic uveitis ana
toxicity, Punctal stenosis and reversible punctate deep stromal infection, has not been established.
epithelial keratitis with crystulline deposits have each Unlike vidarabine, trifluridine cannot be used
been reported in 1 patient after 21 days of treatment systemically for these conditions.
(Hyndiuk et al., 1978; Travers and Patterson, 1978). While trifluridine is useful in treating the recur-
Trifluridine: A Review 350

rent ulcers which occur with herpetic ocular disease, Cheng, Y.C.; Goz, B.; Neenan, J.P.; Ward, D.C. and Prusoff,
it is unlikely that this or other antiviral drugs would W.H.: Selective inhibition of herpes sinplex virus by 5'-
amino-2',5'-dideoxy-5-iodouridine. Journal of Virology 15:
affect the incidence of these recurrences, in view of
1284-1285 (1975).
the evidence for the latency-reactivation cycle of Cirkel, P.K.S. and van Ketel, W.G.: Allergic contact dermatitis to
herpes simplex (see section 3.1.3). trifluorothymidine eyedrops. Contact Dermatitis 7: 49-50
With only a few drugs available commercially for (1981).
treating herpetic keratitis, trifluridine significantly ex- Clough, D.W.; Wigdahl, B.L. and Parkhurst, J.R.: Biological
effects of 5-carboxy-2'-deoxyuridine: hydrolysis product of 5-
pands the armamentarium. Importantly, it can often
trifluoromethyl-2'-deoxyuridine. Antimicrobial Agents and
be used successfully in patients unresponsive to idox- Chemotherapy 14: 126-131 (\978).
uri dine or vidarabine, or intolerant of idoxuridine. Collins, P. and Bauer, DJ.: Relative potencies of anti-herpes com-
pounds. Annals of the New York Academy of Sciences 284:
49-59 (l977a).
Collins, P. and Bauer, DJ.: Comparison of activity of herpes
6. Dosage and Administration
virus inhibitors. Journal of Antimicrobial Chemotherapy 3:
(Suppl. A): 73-81 (\977b).
The recommended dosage of trifluridine I % oph- Collins, P. and Bauer, DJ.: The activity in vitro against herpes
thalmic solution for the treatment of herpetic keratitis virus of 9.(2-hydroxyethoxymethyl)guanine (acycloguanosine),
is I drop on the affected cornea every 2 hours while a new antiviral agent. Journal of Antimicrobial Chemotherapy
5: 431-436 (1979).
awake (with a maximum of 9 drops/day) until the
Coster, DJ.; Jones, B.R. and McGill, 1.1.: Treatment of amoeboid
cornea has completely re-epithelialised. Following herpetic ulcers with adenine arabinoside or trifluorothymidine.
this, 1 drop 4-hourly (with a minimum of 5 British Journal of Ophthalmology 63: 418-421 (1979).
drops/day) should be given for 7 days. However, the Coster, DJ.; McKinnon, J.R.; McGill, 1.1.; Jones, B.R. and
manufacturer recommends that continuous treatment Fraunfelder, F.T.: Clinical evaluation of adenine arabinoside
and trifluorothymidine in the treatment of corneal ulcers
should not exceed 21 days because of potential ocular
caused by herpes simplex virus. Journal of Infectious Diseases
toxicity. In fact, if there is no improvement after 7 113 (SuppU: AI73-AI77 (1976).
days, or re-epithelialisation is not complete within 14 Darougar, S.; Hunter, P.A.; Viswalingam, M.; Gibson, 1.A. and
days, the treatment may need to be changed. Jones, B.R.: Acute follicular conjunctivitis and keratocon-
junctivitis due to herpes simplex virus in London. British Jour-
nal of Ophthalmology 62: 843-849 (1978).
Darougar, S.; Quinlan, M.P.; Gibson, J.A.; Jones, B.R. and
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