Trifluridine and tipiracil

Trifluridine and tipiracil Uses, Dosage, Side Effects, Food Interaction and all others data.

Tipiracil is a thymidine phosphorylase inhibitor. It is used in combination with trifluridine, in a ratio of 1:0.5, to form TAS-102. The main function of Tipiracil in TAS-102 is to increase trifluridine bioavailability by inhibiting its catabolism. TAS-102 is indicated for the treatment of metastatic colorectal cancer which has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, or with an anti-VEGF or anti-EGFR therapy.

Tipiracil prevents trifluridine conversion into 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, which is an inactive major metabolite, by inhibiting the enzyme thymidine phosphorylase. Thus, tipiracil is able to increase trifluridine bioavailability. On the other hand, thymidine phsophorylase is a known platelet-derived endothelial cell growth factor and its inhibition generates an indirect antiangiogenic benefit.

Trifluridine is a fluorinated pyrimidine nucleoside analog which interferes with DNA synthesis of herpes simplex virus, type 1 and 2 and vaccinia virus. It stops replication of herpes viral DNA in 3 ways:

Competitive inhibition of viral DNA polymerase,Incorporation into and termination of the growing viral DNA chain andInactivation of the viral DNA polymerase.Trifluridine 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 . Trifluridine 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 .

Trifluridine and tipiracil
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Trifluridine and tipiracil
Generic	Tipiracil + trifluridine
Type	Oral
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Tipiracil is a thymidine phosphorylase inhibitor used as an adjunct treatment of adult patients with certain types of gastric or colorectal malignancies.

Tipiracil, in combination with trifluridine, is indicated for the treatment of refractory mestastatic colorectal cancer patients who keep progressing despite of treatment with standard chemotherapy and biologics.

Trifluridine Sterile Eye Drops is used for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, type 1 and 2.

Trifluridine and tipiracil is also used to associated treatment for these conditions: Metastatic Colorectal Cancer (MCRC)Metastatic Colorectal Cancer (MCRC), Primary keratoconjunctivitis caused by herpes simplex virus type 2, Recurrent epithelial keratitis caused by herpes simplex 2, Vaccinia infection in the cornea and conjunctiva, Vaccinia virus ophthalmic infections

How Trifluridine and tipiracil works

Tipiracil is a thymidine phosphorylase inhibitor. Its function prevents the breakdownof the active component of trifluridine, thus increasing the bioavailability of trifluridine and boosting its systemic presence. In addition, it is reported that thymidine phosphorylase is an angiogenic factor usually overexpressed in solid tumors. There is a direct association of thymidine phosphorylase with a poor prognosis; where the tumors with an elevated expression of this enzyme tend to present an increased angiogenesis and ergo, be more malignant. Therefore, it has been suggested that tipiracil presents an aditional function by downregulating tumoral angiogenesis.

The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine 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 . Trifluridine 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 .

Dosage

Trifluridine and tipiracil dosage

Children above 6 years of age & adults: Instill 1 drop every 2 hrs while awake; maximum 9 drops/day until the corneal ulcer has completely re-epithelialized.

After re-epithelialization: Instill 1 drop every 4 hrs or at least 5 drops/day for 7 days is recommended. If there are no signs of improvement after 7 days of therapy or complete re-epithelialization has not occurred after 14 days of therapy, other forms of therapy should be considered. Continuous administration of Trifluridineeye drops for periods exceeding 21 days should be avoided because of potential ocular toxicity.

Side Effects

Reported side effects are mild, transient burning or stinging sensation upon instillation. Other side effects are superficial punctate keratopathy, epithelial keratopathy, hypersensitivity reaction, stromal edema, irritation, keratitis sicca, hyperemia and increased intraocular pressure.

Toxicity

TAS-102 is a cytotoxic drug, therefore this combination drug can cause myelosupression, including neutropenia, anemia, thrombocytopenia, and febrile neutropenia. According to pre-clinical studies, TAS-102 presents also embryo-fetal 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 .

Precaution

Trifluridine should be prescribed only for patients who have a clinical diagnosis of herpetic keratitis.

Volume of Distribution

After a single TAS-102 dose if 35 mg/m2 in patients with advanced solid tumors, it was recorded a volume of distribution of tipiracil of 333 L.

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 .

Elimination Route

Absorption of tipiracil is suggested to be done by the gastrointestinal tract. Administration of a single 35 mg/m2 dose of TAS-102 containing tipiracil and trifluridine, generates the absoprtion rates of tipiracil of AUC 301 ng h/ml, maximum observed plasma concentration (Cmax) 69 ng/ml and time for maximum observed plasma concentration (Tmax) 3 h. The consumption of a high-fat and high-calorie meal can decrease Cmax and AUC by 40%.

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. Trifluridine 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 .

Half Life

Tipiracil mean elmination half-life is 2.1 hours.

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

A single 35mg/m2 of TAS-102 in patients with advanced solid tumors produces a clearance rate of tipiracil of 109 L/hr, with a recovery rate of 77% of the total dose.

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.

Elimination Route

The main fraction of tipiracil is excreted unchanged in the mainly in the faeces (49.7%) followed by the urine (27%). From the urine excretion 79.1% is accounted by unchanged tipiracil while 14% is 6-HMU. On the other hand, the faeces elimination analysis was formed by 48.2% unchanged tipiracil and 34.4% 6-HMU.

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 .

Pregnancy & Breastfeeding use

Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Trifluridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: It is unlikely that Trifluridine is excreted in human milk after instillation of Trifluridine eye drops because of the relatively small dosage. The drug should not be prescribed for nursing mothers unless the potential benefits outweigh the potential risks.