Usage
Tipiracil is used in combination with trifluridine for the treatment of adult patients with:
- Metastatic colorectal cancer (mCRC): As a single agent or in combination with bevacizumab, in patients 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.
- Metastatic gastric or gastroesophageal junction adenocarcinoma: In patients previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.
Pharmacological Classification: Tipiracil is an antineoplastic antimetabolite, specifically a thymidine phosphorylase inhibitor. It is only used in combination with trifluridine.
Mechanism of Action: Tipiracil itself doesn’t have anticancer activity. It inhibits the enzyme thymidine phosphorylase, which is responsible for the breakdown of trifluridine. By inhibiting this enzyme, tipiracil increases the amount of trifluridine available to exert its anticancer effects. Trifluridine is incorporated into DNA, interfering with DNA synthesis and function, ultimately leading to cancer cell death.
Alternate Names
While Tipiracil itself doesn’t have other names, the combination with trifluridine is known as trifluridine/tipiracil.
Brand Name: Lonsurf
How It Works
Pharmacodynamics: Tipiracil increases trifluridine exposure by inhibiting thymidine phosphorylase. Trifluridine is a thymidine-based nucleoside analog. It is phosphorylated intracellularly to its active form, trifluridine triphosphate (TFTP), which is incorporated into DNA, interfering with DNA synthesis and repair and leading to cell death.
Pharmacokinetics:
- Absorption: Tipiracil is rapidly absorbed after oral administration. Taking it with food increases its absorption.
- Metabolism: Tipiracil is not extensively metabolized by cytochrome P450 enzymes.
- Elimination: Primarily renal excretion.
Mode of Action: Tipiracil increases the bioavailability of trifluridine, allowing it to be incorporated into DNA. Trifluridine is a pyrimidine analog that inhibits thymidylate synthase, leading to DNA damage and ultimately apoptosis.
Receptor Binding, Enzyme Inhibition: Tipiracil is a thymidine phosphorylase inhibitor. Trifluridine doesn’t involve specific receptor binding but interacts with thymidylate synthase.
Elimination Pathways: Primarily renal excretion for both tipiracil and trifluridine.
Dosage
Tipiracil is always given in combination with trifluridine. Dosage is based on the trifluridine component.
Standard Dosage
Adults:
- 35 mg/m² of trifluridine (combined with the appropriate amount of tipiracil as found in Lonsurf tablets) orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle.
- The dose should not exceed 80 mg of trifluridine per dose.
Children:
The safety and efficacy of trifluridine/tipiracil have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No starting dose adjustment is required. However, elderly patients may be more susceptible to myelosuppression. Close monitoring of blood counts is recommended.
- Patients with Renal Impairment: No dose adjustment is recommended for mild renal impairment. Use is not recommended in patients with end-stage renal disease.
- Patients with Hepatic Dysfunction: No dose adjustment is recommended for mild hepatic impairment. Use is not recommended for moderate or severe hepatic impairment.
- Patients with Comorbid Conditions: Exercise caution in patients with pre-existing myelosuppression or those receiving myelosuppressive therapy.
Clinical Use Cases
Trifluridine/tipiracil is specifically indicated for metastatic colorectal cancer and metastatic gastric or gastroesophageal junction adenocarcinoma in patients who have received prior therapies. It is not indicated for use in other settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reduction may be required based on individual safety and tolerability. A maximum of three dose reductions are permitted, to a minimum dose of 20 mg/m² twice daily. Dose escalation is not permitted after it has been reduced. Specific dose adjustment guidelines should be consulted based on the severity of adverse effects, particularly myelosuppression.
Side Effects
Common Side Effects
- Neutropenia
- Anemia
- Thrombocytopenia
- Fatigue
- Nausea
- Decreased appetite
- Diarrhea
- Vomiting
- Abdominal pain
- Pyrexia
Rare but Serious Side Effects
- Febrile neutropenia
- Interstitial lung disease
- Severe allergic reactions
Long-Term Effects
Long-term effects are not well-established as the drug is used for advanced cancers. However, potential long-term complications might include persistent myelosuppression.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe myelosuppression (neutropenia, anemia, thrombocytopenia), requiring monitoring and potential dose adjustments or discontinuation.
Contraindications
- Hypersensitivity to trifluridine, tipiracil, or any component of the formulation.
Drug Interactions
No formal pharmacokinetic drug interaction studies have been conducted. However, avoid concomitant use with human thymidine kinase substrate antivirals (e.g., zidovudine, stavudine).
Pregnancy and Breastfeeding
- Pregnancy: Trifluridine/tipiracil can cause fetal harm. Females of reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose.
- Breastfeeding: It is not known if trifluridine/tipiracil is present in breast milk. Breastfeeding is not recommended during treatment and for 1 day after the last dose.
Drug Profile Summary
- Mechanism of Action: Tipiracil enhances trifluridine efficacy by inhibiting its degradation, allowing for increased incorporation into DNA, disrupting DNA synthesis and function.
- Side Effects: Common: Myelosuppression (neutropenia, anemia, thrombocytopenia), fatigue, nausea, diarrhea. Serious: Febrile neutropenia.
- Contraindications: Hypersensitivity.
- Drug Interactions: Limited data available. Avoid concomitant use with thymidine kinase substrate antivirals.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy. Not recommended while breastfeeding.
- Dosage: 35 mg/m² trifluridine twice daily on Days 1-5 and 8-12 of a 28-day cycle. Max 80mg/dose trifluridine.
- Monitoring Parameters: Complete blood counts (CBC) including absolute neutrophil count (ANC) and platelet counts.
Popular Combinations
Trifluridine/tipiracil can be used in combination with bevacizumab for metastatic colorectal cancer.
Precautions
- General Precautions: Monitor for myelosuppression.
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Not recommended.
- Children & Elderly: No pediatric data. Elderly patients are at increased risk of myelosuppression.
- Lifestyle Considerations: No specific lifestyle restrictions have been identified.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tipiracil/Trifluridine in mCRC?
A: 35 mg/m² of trifluridine (in combination with tipiracil as in Lonsurf) orally twice daily with food on Days 1-5 and 8-12 of a 28-day cycle. Maximum dose: 80 mg trifluridine per dose.
Q2: How does Tipiracil work with Trifluridine?
A: Tipiracil inhibits thymidine phosphorylase, preventing the breakdown of trifluridine and increasing its availability to exert anticancer effects.
Q3: What are the most common side effects?
A: Myelosuppression (neutropenia, anemia, thrombocytopenia), fatigue, nausea, decreased appetite, and diarrhea are common side effects.
Q4: What are the contraindications for Tipiracil/Trifluridine?
A: Hypersensitivity to either drug or any component of the formulation.
Q5: Can Tipiracil/Trifluridine be used in pregnant or breastfeeding women?
A: Contraindicated in pregnancy due to potential fetal harm. Breastfeeding is not recommended.
Q6: Are there any specific monitoring parameters for patients on this drug?
A: Closely monitor complete blood counts (CBCs), especially neutrophil and platelet counts due to the risk of myelosuppression. Monitor before each cycle, on Day 15 of each cycle, and as clinically indicated.
Q7: How should Tipiracil/Trifluridine be administered?
A: Orally, twice daily, with food.
Q8: Are there any dosage adjustments for elderly patients?
A: No initial dose adjustment is necessary but monitor closely for myelosuppression, which is more common in elderly patients.
Q9: Can Tipiracil/Trifluridine be used in patients with renal impairment?
A: No dose adjustment is recommended for mild renal impairment. Use is not recommended in patients with end-stage renal disease. Caution is advised in patients with moderate renal impairment.
Q10: What is the role of Tipiracil in the combination?
A: Tipiracil does not have direct anticancer activity. Its role is to inhibit the breakdown of trifluridine, increasing its efficacy.
