Usage
Tipiracil + Trifluridine is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. It is also approved for metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who have had two or more prior treatment regimens.
This drug is classified as an antineoplastic antimetabolite.
Tipiracil + Trifluridine works through a dual mechanism. Trifluridine, a nucleoside analog, incorporates into DNA, leading to DNA dysfunction and ultimately cell death. Tipiracil inhibits the enzyme thymidine phosphorylase, which degrades trifluridine, thereby increasing trifluridine’s availability and enhancing its anticancer effects.
Alternate Names
The combination is often referred to as TAS-102.
A popular brand name is Lonsurf®.
How It Works
Pharmacodynamics: Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, causing DNA damage and inhibiting cell proliferation. Tipiracil enhances trifluridine’s activity by inhibiting thymidine phosphorylase, the enzyme responsible for trifluridine’s degradation.
Pharmacokinetics: Trifluridine is rapidly absorbed after oral administration, with peak plasma concentrations occurring within two hours. Tipiracil is also well-absorbed orally. Both drugs are primarily metabolized in the liver and are eliminated primarily through renal excretion. The half-life of Trifluridine is approximately 1.4 hours, while the half-life of Tipiracil is around 2.1 hours.
Mode of Action: Trifluridine acts by being incorporated into DNA, where it acts as an antimetabolite. Tipiracil inhibits thymidine phosphorylase, reducing Trifluridine’s degradation and increasing its concentration in the body.
Elimination Pathways: Both drugs are predominantly excreted by the kidneys, but some hepatic metabolism is also involved.
Dosage
Standard Dosage
Adults:
The recommended dose is 35 mg/m² orally twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. The maximum dose per administration is 80 mg (based on the trifluridine component). Treatment continues until disease progression or unacceptable toxicity.
Children:
The safety and efficacy of Tipiracil + Trifluridine have not been established in pediatric patients.
Special Cases:
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Elderly Patients: No specific dose adjustments are required based solely on age. However, close monitoring for adverse effects is advised.
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Patients with Renal Impairment: For patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), the recommended dose is 20 mg/m² twice daily. For severe renal impairment (creatinine clearance less than 30 mL/min), the drug is not recommended.
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Patients with Hepatic Dysfunction: For patients with moderate hepatic impairment, the recommended starting dose is 20 mg/m² twice daily. For severe hepatic impairment, the drug is not recommended.
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Patients with Comorbid Conditions: Caution is advised in patients with severe myelosuppression.
Clinical Use Cases
The provided sources do not list specific dosages for the following clinical scenarios:
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations (e.g., status epilepticus, cardiac arrest)
It is important to note that Tipiracil + Trifluridine is not indicated for these situations.
Dosage Adjustments
Dose adjustments are recommended for patients with renal or hepatic impairment, as detailed above. Dose reductions may also be considered for patients experiencing severe adverse reactions.
Side Effects
Common Side Effects
Neutropenia, anemia, thrombocytopenia, nausea, vomiting, fatigue, diarrhea, abdominal pain, decreased appetite, fever.
Rare but Serious Side Effects
Febrile neutropenia, intestinal perforation, severe infections, and other serious hematologic toxicities.
Long-Term Effects
Long-term effects are primarily related to myelosuppression.
Adverse Drug Reactions (ADR)
Myelosuppression, including neutropenia, anemia, and thrombocytopenia, are clinically significant ADRs and require close monitoring.
Contraindications
Hypersensitivity to Tipiracil or Trifluridine. Severe renal or hepatic impairment.
Drug Interactions
Concomitant use with other myelosuppressive drugs can increase the risk of hematologic toxicities.
Pregnancy and Breastfeeding
Tipiracil + Trifluridine is contraindicated during pregnancy due to its potential for teratogenic effects. It is unknown whether the drug is excreted in breast milk; breastfeeding should be discontinued during treatment.
Drug Profile Summary
- Mechanism of Action: Dual mechanism: Trifluridine is a nucleoside analog that incorporates into DNA; Tipiracil inhibits thymidine phosphorylase, increasing Trifluridine levels.
- Side Effects: Neutropenia, anemia, thrombocytopenia, nausea, vomiting, fatigue.
- Contraindications: Hypersensitivity, severe renal/hepatic impairment, pregnancy.
- Drug Interactions: Other myelosuppressive agents.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding should be discontinued.
- Dosage: 35 mg/m² BID on Days 1-5 and 8-12 of a 28-day cycle; max 80 mg/dose.
- Monitoring Parameters: Complete blood counts, renal and liver function tests.
Popular Combinations
Tipiracil + Trifluridine is sometimes used in combination with bevacizumab in certain cases of metastatic colorectal cancer.
Precautions
Monitor closely for myelosuppression. Use with caution in patients with pre-existing renal or hepatic dysfunction.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tipiracil + Trifluridine?
A: 35 mg/m² orally twice daily on Days 1-5 and 8-12 of a 28-day cycle, not to exceed 80 mg/dose. Dose reductions are necessary for patients with moderate renal or hepatic impairment.
Q2: What is the mechanism of action of this combination?
A: Trifluridine incorporates into DNA, causing damage. Tipiracil inhibits thymidine phosphorylase, increasing Trifluridine’s concentration.
Q3: What are the most common side effects?
A: Myelosuppression (neutropenia, anemia, thrombocytopenia), nausea, vomiting, fatigue, and diarrhea.
Q4: What are the contraindications for Tipiracil + Trifluridine?
A: Hypersensitivity, severe renal or hepatic impairment, and pregnancy.
Q5: Are there any specific drug interactions?
A: Concomitant use with other myelosuppressive agents can worsen hematologic toxicity.
Q6: Can this drug be used during pregnancy or breastfeeding?
A: No, it is contraindicated during pregnancy and breastfeeding should be discontinued while on treatment.
Q7: What monitoring parameters are important during treatment?
A: Regular monitoring of complete blood count, renal and liver function tests.
Q8: Is there a maximum dose for Tipiracil + Trifluridine?
A: Yes, the maximum single dose is 80mg, based on the trifluridine component.
Q9: What is the drug’s brand name?
A: Lonsurf®
Q10: What should I do if a dose is missed?
A: Do not make up for the missed dose. Resume with the next scheduled dose.
