Usage
Pegylated liposomal irinotecan, in combination with fluorouracil (5-FU) and leucovorin (LV), is indicated for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. It has also been recently approved, in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX), for the first-line treatment of adults with metastatic pancreatic adenocarcinoma. It is not indicated as a single agent.
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Pharmacological Classification: Antineoplastic agent, topoisomerase I inhibitor.
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Mechanism of Action: Pegylated liposomal irinotecan is a liposomal formulation of irinotecan, which itself is a prodrug. The liposomal encapsulation allows for enhanced delivery and accumulation of irinotecan within the tumor. Inside the tumor cells, irinotecan is converted to SN-38, its active metabolite. SN-38 inhibits topoisomerase I, an enzyme essential for DNA replication and repair. This inhibition leads to DNA damage, ultimately causing cell death.
Alternate Names
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Liposomal irinotecan
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nal-IRI
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MM-398
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PEP02
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Brand Names: ONIVYDE®
How It Works
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Pharmacodynamics: The primary effect of pegylated liposomal irinotecan is cytotoxicity against tumor cells due to topoisomerase I inhibition by SN-38. The liposomal encapsulation enhances drug delivery to the tumor site due to factors like enhanced permeability and retention (EPR) effect and uptake by tumor-associated macrophages.
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Pharmacokinetics: The pegylated liposomal formulation alters the pharmacokinetics of irinotecan. This formulation results in prolonged circulation time, increased tumor uptake, and reduced plasma clearance compared to conventional irinotecan. Irinotecan is metabolized in the liver to SN-38, its active metabolite. SN-38 subsequently undergoes glucuronidation by UGT1A1 enzymes.
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Mode of Action: Irinotecan is converted to SN-38, which forms a ternary complex with topoisomerase I and DNA. This complex leads to DNA single-strand breaks. During replication, these breaks become double-strand breaks, which ultimately trigger cell death.
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Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: SN-38 inhibits topoisomerase I.
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Elimination Pathways: Irinotecan and SN-38 are primarily eliminated through biliary/fecal excretion and hepatic metabolism, with renal excretion playing a lesser role.
Dosage
Standard Dosage
- 70 mg/m² intravenously over 90 minutes, followed by LV 400 mg/m² intravenously over 30 minutes, followed by 5-FU 2400 mg/m² intravenously over 46 hours, administered every 2 weeks.
- Patients homozygous for the UGT1A1*28 allele: Initial dose of 50 mg/m² every 2 weeks, with escalation to 70 mg/m² as tolerated.
- 50 mg/m² intravenously over 90 minutes, followed by oxaliplatin 60 mg/m² intravenously over 120 minutes, followed by leucovorin 400 mg/m² intravenously over 30 minutes, followed by fluorouracil 2400 mg/m² intravenously over 46 hours, administered every 2 weeks (NALIRIFOX).
Children: No established pediatric dosing.
Special Cases:
- Elderly Patients: No specific dose adjustments based on age, but close monitoring for adverse events is recommended.
- Patients with Renal Impairment: No dose adjustment needed for mild to moderate impairment. Use with caution in severe renal impairment. Not recommended for patients with creatinine clearance <30 mL/min.
- Patients with Hepatic Dysfunction: No dose recommendations for patients with bilirubin >ULN. Use with caution in patients with hepatic impairment.
- Patients with Comorbid Conditions: Use with caution in patients with pre-existing lung disease. Close monitoring is recommended for patients with cardiovascular conditions or diabetes.
Clinical Use Cases
Pegylated liposomal irinotecan is specifically indicated for metastatic pancreatic adenocarcinoma, in combination with 5-FU/LV (second-line) or NALIRIFOX (first-line). It does not have specific dosages for other clinical use cases such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions may be necessary based on toxicity. All dose modifications should be based on the worst preceding toxicity. (See Tables 3 and 4, Source [11]).
Side Effects
Common Side Effects
Diarrhea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anemia, stomatitis, and pyrexia.
Rare but Serious Side Effects
Severe neutropenia (including febrile neutropenia and sepsis), severe diarrhea, interstitial lung disease, hypersensitivity reactions (including anaphylaxis), and embryo-fetal toxicity.
Long-Term Effects
Chronic complications from prolonged use are not fully characterized but may include secondary malignancies.
Adverse Drug Reactions (ADR)
Severe neutropenia, severe diarrhea, interstitial lung disease, and hypersensitivity reactions require immediate intervention.
Contraindications
History of severe hypersensitivity to irinotecan or any component of the formulation. Breastfeeding.
Drug Interactions
- Strong CYP3A4 Inducers: Avoid concomitant use or discontinue at least 2 weeks prior to starting pegylated liposomal irinotecan.
- Strong CYP3A4 or UGT1A1 Inhibitors: Avoid concomitant use or discontinue at least 1 week prior to starting therapy.
- Other Chemotherapy: Use with caution in patients who have recently received other chemotherapy or radiotherapy.
Other potential interactions may exist. Consult drug information resources for a comprehensive list.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated in pregnancy. Can cause fetal harm.
- Breastfeeding: Contraindicated during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Topoisomerase I inhibitor.
- Side Effects: Diarrhea, neutropenia, nausea, vomiting, fatigue.
- Contraindications: Hypersensitivity to irinotecan, breastfeeding.
- Drug Interactions: Strong CYP3A4 inducers and inhibitors, UGT1A1 inhibitors.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Refer to detailed dosage guidelines above.
- Monitoring Parameters: Complete blood counts (CBC), liver function tests (LFTs), renal function tests (RFTs), and monitor for signs and symptoms of diarrhea and hypersensitivity.
Popular Combinations
- 5-FU/LV (second-line treatment for metastatic pancreatic adenocarcinoma).
- NALIRIFOX (oxaliplatin, 5-FU/LV) (first-line treatment for metastatic pancreatic adenocarcinoma).
Precautions
- General Precautions: Monitor for myelosuppression, diarrhea, and hypersensitivity reactions. Pre-medication with corticosteroids and antiemetics is recommended.
- Specific Populations: Contraindicated in pregnant and breastfeeding women. Use with caution in patients with renal or hepatic impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pegylated Liposomal Irinotecan?
A: Refer to detailed dosage guidelines above.
Q2: What is the mechanism of action of Pegylated Liposomal Irinotecan?
A: It is a topoisomerase I inhibitor. Its active metabolite, SN-38, causes DNA damage leading to cell death. Liposomal delivery enhances tumor uptake.
Q3: What are the most common side effects?
A: Diarrhea, neutropenia, nausea, vomiting, fatigue, asthenia, anemia, stomatitis, and pyrexia.
Q4: Is Pegylated Liposomal Irinotecan safe during pregnancy?
A: No. It is contraindicated in pregnancy due to risk of fetal harm.
Q5: What are the major drug interactions to be aware of?
A: Strong CYP3A4 inducers and inhibitors, and UGT1A1 inhibitors.
Q6: How is Pegylated Liposomal Irinotecan administered?
A: Intravenous infusion.
Q7: What should be monitored during treatment?
A: CBCs, LFTs, and RFTs, and monitor for signs of diarrhea, neutropenia, and hypersensitivity reactions.
Q8: Can Pegylated Liposomal Irinotecan be used as a single agent?
A: No. It is always used in combination regimens.
Q9: What are the signs and symptoms of a hypersensitivity reaction?
A: Rash, hives, itching, shortness of breath, facial swelling, and hypotension. Seek immediate medical attention if these occur.
Q10: What are the dose modifications for patients with UGT1A1*28 polymorphism?
A: A reduced starting dose is recommended, with potential escalation based on individual patient tolerance.
