Introduction
Fludin Ophthalmic Solution 1% is a fluorinated pyrimidine nucleoside that is structurally related to idoxuridine . It is an active antiviral agent in ophthalmic solutions used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus. It displays effective antiviral activity against Herpes simplex virus type 1 and 2 .
It used for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. In the anticancer therapy, trifluridine acts as a thymidine-based nucleoside metabolic inhibitor that gets incorporated into DNA of cancer cells following cell uptake to aberrate DNA function during cell replication .
Uses
Fludin Ophthalmic Solution 1% is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal cancers.
Fludin Ophthalmic Solution 1% is used for the treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2 in ophthalmic solutions.
Fludin Ophthalmic Solution 1%, in combination with tipiracil as oral tablets, is indicated for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy .
Associated Conditions
Pharmacodynamics
Fludin Ophthalmic Solution 1% exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo . Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro . While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials . In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines . The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA . Fludin Ophthalmic Solution 1% and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice .
In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo . In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo . Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec .
Mechanism of Action
The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Fludin Ophthalmic Solution 1% gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Fludin Ophthalmic Solution 1% also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form . Subsequent phosphorylation produces trifluridine triphosphate , which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation . As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine . Fludin Ophthalmic Solution 1% monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines . Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU) . However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells .
Absorption
Systemic absorption of trifluridine following therapeutic dosing with ophthalmic trifluridine appears to be negligible .
At least 57% of the orally-administered trifluridine is absorbed . Following twice daily oral dosing of trifluridine in combination with tipiracil, systemic exposure of trifluridine increased more than dose-proportionally over the dose range of 15 to 35 mg/m^2. Fludin Ophthalmic Solution 1% accumulation was 3-fold for AUC0-last and 2-fold for peak plasma concentration (Cmax) at steady state . The time to reach the peak plasma concentrations (Cmax) was 2 hours . Tipiracil increases the AUC and Cmax of trifluridine. Food intake was shown to decrease the Cmax and AUC compared to those in a fasting state .
Volume of Distribution
Following a single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L .
Protein Binding
In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil .
Route of Elimination
About 55% of the total recovered radio-labelled trifluridine was detected in the urine within 24 hours . Following oral administration of trifluridine in combination with tipiracil, only 3% of the total dose was excreted into faeces and expired air . Administration of a 60mg single oral dose of the combination product resulted in the mean urinary recovery of 1.5% of unchanged trifluridine and 19.2% for the inactive metabolite FTY after the 48-hour cumulative excretion .
Half Life
The half life is 12 to 18 minutes following ophthalmic administration .
After administration of trifluridine with tipiracil at oral doses 35 mg/m^2 twice daily, the mean elimination half-life (t1/2) of trifluridine was 1.4 hours following a single dose . At steady state, the mean elimination half-life was 2.1 hours .
Clearance
Following a single dose of Lonsurf (35 mg/m^2) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 L/hr.
Toxicity
Intravenous LD50 in rat was 2946 mg/kg . Oral LD50 in rat and mouse were > 4379mg/kg . Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications . Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients .
Food Interactions
- Take with food.
