Trifluridine + Tipiracil

Trifluridine + 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 + 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 + Tipiracil
Generic	Trifluridine + Tipiracil
Type
Therapeutic Class
Manufacturer
Available Country	Bangladesh
Last Updated:	September 24, 2024 at 5:38 am

Uses

Metastatic Colorectal Cancer: Trifluridine and Tipiracil is indicated for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin-and irinotecanbased chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, ... Read more

Trifluridine + 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 + 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 + Tipiracil dosage

The recommended dosage of Trifluridine and Tipiracil is 35 mg/m2 up to a maximum of 80 mg per dose (based on the Trifluridine component) orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Round dose to the nearest 5 mg increment. Instruct patients to swallow the tablet whole. Instruct patients not to retake doses of Trifluridine and Tipiracil that are vomited or missed and to continue with the next scheduled dose. Trifluridine and Tipiracil is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Side Effects

The most common adverse reactions or laboratory abnormalities (≥10%) are anemia, neutropenia, fatigue/ asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, and pyrexia.

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

Severe Myelosuppression: In the 868 patients who received Trifluridine and Tipiracil in RECOURSE and TAGS, Trifluridine and Tipiracil caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3%). Two patients (0.2%) died due to neutropenic infection/sepsis and four other patients (0.5%) died due to septic shock. A total of 12% of Trifluridine and Tipiracil-treated patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on Day 15 of each cycle of Trifluridine and Tipiracil and more frequently as clinically indicated. Withhold Trifluridine and Tipiracil for severe myelosuppression and resume at the next lower dosage.Embryo-Fetal Toxicity: Based on animal studies and its mechanism of action, Trifluridine and Tipiracil can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dosage levels resulting in exposures lower than those achieved at the recommended dosage of 35 mg/m2 twice daily. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with Trifluridine and Tipiracil and for at least 6 months after the final dose.

Interaction

In vitro studies indicated that Trifluridine, Tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6, or CYP3A4/5. In vitro studies indicated that Trifluridine was not an inhibitor of or substrate for human uptake and efflux transporters.

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: Based on animal data and its mechanism of action Trifluridine and Tipiracil can cause fetal harm.Lactation: There are no data on the presence of Trifluridine, Tipiracil or its metabolites in human milk or its effects on the breastfed child or on milk production.Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Trifluridine and Tipiracil.Contraception: Trifluridine and Tipiracil can cause fetal harm when administered to a pregnant woman.Females: Advise females of reproductive potential to use effective contraception during treatment with Trifluridine and Tipiracil and for at least 6 months after the final dose.Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with Trifluridine and Tipiracil and for at least 3 months after the final dose.

Contraindication

Contraindicated in patients who develop hypersensitivity reactions or chemical intolerance to Trifluridine.

Special Warning

Patients with Renal Impairment: In a dedicated renal impairment study, all patients received Trifluridine and Tipiracil 35 mg/m2 twice daily except for patients with severe renal impairment who received 20 mg/m2 twice daily. Mild renal impairment (CrCl of 60 to 89 mL/min as determined by the Cockcroft-Gault formula) had no clinically important effect on steady-state AUC0-last of trifluridine and tipiracil. Moderate renal impairment (CrCl of 30 to 59 mL/min) increased steady-state AUC0-last of Trifluridine by 56% and Tipiracil by 139% compared to normal renal function (CrCl ≥ 90 mL/min). Severe renal impairment (CrCl of 15 to 29 mL/min) increased the dose-normalized steady-state AUC0-last of Trifluridine by 140% and Tipiracil by 614% compared to normal renal function. The pharmacokinetics of Trifluridine and Tipiracil have not been studied in patients with end stage renal disease. Patients with Hepatic Impairment: No clinically important differences in the mean exposures of Trifluridine and Tipiracil were observed between patients with mild hepatic impairment (total bilirubin ≤ULN and AST > ULN or total bilirubin <1 to 1.5 times ULN and any AST) to moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST) and patients with normal hepatic function (total bilirubin and AST ≤ ULN); however, 5 of 6 patients with moderate hepatic impairment experienced Grade 3 or 4 increased bilirubin levels. The pharmacokinetics of Trifluridine and Tipiracil have not been studied in patients with severe hepatic impairment.Pediatric Use: Safety and effectiveness of Trifluridine and Tipiracil in pediatric patients have not been established.Geriatric Use: No overall differences in effectiveness were observed in patients 65 or older versus younger patients.