Usage
Trabectedin is an antineoplastic agent, specifically classified as an alkylating agent, indicated for the treatment of:
- Soft Tissue Sarcoma: Unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen.
- Ovarian Cancer: (in combination with pegylated liposomal doxorubicin). Relapsed platinum-sensitive ovarian cancer.
Trabectedin exerts its antitumor activity by binding to the minor groove of DNA, bending DNA, and interfering with several transcription factors, DNA binding proteins, and DNA repair pathways. This ultimately leads to cell cycle arrest and apoptosis (programmed cell death) of tumor cells.
Alternate Names
- International Nonproprietary Name (INN): Trabectedin
- Brand Name: Yondelis
How It Works
Pharmacodynamics: Trabectedin binds to the minor groove of DNA, causing DNA bending and interfering with DNA-binding proteins and DNA repair pathways. This leads to cell cycle arrest and apoptosis in susceptible cells, particularly in rapidly dividing cancer cells.
Pharmacokinetics:
- Absorption: When administered intravenously, trabectedin exhibits rapid distribution.
- Metabolism: Primarily metabolized by the liver via cytochrome P450 3A4 (CYP3A4) enzymes.
- Elimination: Primarily eliminated through hepatic metabolism and biliary excretion. A small percentage is excreted in the urine.
Mode of Action:
Trabectedin’s primary mechanism of action involves binding to the N2 of guanine in the DNA minor groove. This leads to DNA bending towards the major groove, interfering with cell cycle progression and several transcription factors and DNA repair pathways. The binding also appears to affect nucleotide excision repair, potentially increasing the drug’s efficacy.
Receptor Binding/Enzyme Inhibition: While trabectedin’s primary mechanism is through DNA binding, it is also known to inhibit several transcription factors, including those involved in cell growth, differentiation, and angiogenesis. The impact on various DNA repair mechanisms contributes to the drug’s cytotoxicity.
Elimination Pathways: Trabectedin is primarily eliminated through the liver (hepatic) via CYP3A4-mediated metabolism and subsequent biliary excretion with some renal excretion in unchanged form.
Dosage
Standard Dosage
Adults:
- Soft Tissue Sarcoma: 1.5 mg/m² administered as a 24-hour intravenous infusion every 3 weeks via a central venous line.
- Ovarian Cancer: 1.1 mg/m² administered as a 3-hour intravenous infusion every 3 weeks immediately after pegylated liposomal doxorubicin (PLD) 30 mg/m².
Premedication with corticosteroids (e.g., dexamethasone 20 mg IV) 30 minutes prior to each trabectedin infusion is required.
Children:
The safety and efficacy of trabectedin have not been established in pediatric patients.
Special Cases:
- Elderly Patients: Clinical experience is limited. Close monitoring is recommended.
- Patients with Renal Impairment: No dose adjustment is recommended for mild to moderate renal impairment (CrCl 30 to 89ml/min). Trabectedin is not recommended for patients with severe renal impairment.
- Patients with Hepatic Dysfunction:
- Moderate: (bilirubin 1.5 - 3 x ULN and AST/ALT < 8 x ULN): 0.9 mg/m² every 3 weeks.
- Severe: (bilirubin > 3 x ULN and any AST/ALT): Contraindicated.
- Patients with Comorbid Conditions: Careful monitoring and dose adjustment may be required for patients with pre-existing cardiac conditions.
Clinical Use Cases
Trabectedin is specifically indicated for the two cancer types mentioned above and has no established role in intubation, surgical procedures, mechanical ventilation, or emergency situations. Its usage is limited to the oncology setting for the approved indications.
Dosage Adjustments
Dose reductions are necessary based on hematologic and non-hematologic toxicities encountered during treatment. Dose delays or reductions may also be required for patients experiencing myelosuppression (decreased blood cell counts), hepatotoxicity, or other significant adverse events.
Side Effects
Common Side Effects
- Neutropenia (low neutrophil count)
- Thrombocytopenia (low platelet count)
- Anemia (low red blood cell count)
- Nausea and vomiting
- Fatigue
- Elevated liver enzymes
- Anorexia (loss of appetite)
- Constipation
- Headache
Rare but Serious Side Effects
- Rhabdomyolysis (muscle breakdown)
- Hepatotoxicity (liver damage), including liver failure
- Cardiomyopathy (heart muscle disease), including heart failure
- Neutropenic sepsis (infection in the setting of low neutrophils)
- Capillary leak syndrome (fluid leakage from capillaries)
- Anaphylaxis (severe allergic reaction)
Long-Term Effects
- Potential for secondary malignancies (other cancers)
- Possible long-term effects on fertility
Adverse Drug Reactions (ADR)
Clinically significant ADRs requiring immediate attention include anaphylaxis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, neutropenic sepsis, capillary leak syndrome, and severe myelosuppression.
Contraindications
- Hypersensitivity to trabectedin
- Severe hepatic impairment (bilirubin > 3 x ULN)
- Pregnancy and breastfeeding
Drug Interactions
- CYP3A4 Inhibitors: Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) may significantly increase trabectedin levels and should be avoided.
- CYP3A4 Inducers: Strong CYP3A4 inducers (e.g., rifampin, phenobarbital, St. John’s Wort) may decrease trabectedin levels and should be avoided.
- Other potential interactions include those with statins, some antibiotics, and antiviral medications.
Pregnancy and Breastfeeding
Trabectedin is contraindicated during pregnancy and breastfeeding due to its potential for serious birth defects and unknown effects on infants. Effective contraception is required for both men and women during and after treatment (3 months for women, 5 months for men).
Drug Profile Summary
- Mechanism of Action: Binds to DNA minor groove, causing bending and interfering with transcription and DNA repair.
- Side Effects: Neutropenia, thrombocytopenia, anemia, nausea/vomiting, fatigue, hepatotoxicity, rhabdomyolysis, cardiomyopathy.
- Contraindications: Hypersensitivity, severe hepatic impairment, pregnancy, breastfeeding.
- Drug Interactions: CYP3A4 inhibitors and inducers.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 1.5 mg/m² every 3 weeks (soft tissue sarcoma); 1.1 mg/m² every 3 weeks (ovarian cancer). Adjustments needed for hepatic impairment.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function tests, CPK levels.
Popular Combinations
Trabectedin is used in combination with pegylated liposomal doxorubicin (PLD) for relapsed platinum-sensitive ovarian cancer.
Precautions
- Monitor for myelosuppression, hepatotoxicity, rhabdomyolysis, cardiomyopathy, and other adverse events.
- Patients with pre-existing cardiac conditions require close monitoring.
- Avoid alcohol consumption during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Trabectedin?
A: For soft tissue sarcoma: 1.5 mg/m² IV over 24 hours every 3 weeks. For ovarian cancer: 1.1 mg/m² IV over 3 hours every 3 weeks after PLD.
Q2: How is Trabectedin administered?
A: As an intravenous infusion over 24 hours (soft tissue sarcoma) or 3 hours (ovarian cancer) via a central venous line.
Q3: What are the most common side effects?
A: Neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue.
Q4: What are the serious side effects to watch for?
A: Rhabdomyolysis, hepatotoxicity, cardiomyopathy, neutropenic sepsis, capillary leak syndrome.
Q5: Can Trabectedin be used during pregnancy or breastfeeding?
A: No, it is contraindicated due to the potential for serious birth defects.
Q6: What are the key drug interactions?
A: Primarily interactions with strong CYP3A4 inhibitors and inducers.
Q7: What premedication is required before Trabectedin infusion?
A: Corticosteroids (e.g., dexamethasone) are mandatory.
Q8: How should I monitor patients receiving Trabectedin?
A: Regular blood tests, including complete blood count, liver function tests, and renal function tests. Monitoring of CPK is important to check for signs of rhabdomyolysis. Regular cardiac assessments may be required for patients with underlying heart conditions.
Q9: Are there any dose adjustments required for elderly patients?
A: While there are no specific dosage adjustments based solely on age, elderly patients should be monitored carefully for adverse events, and dosage adjustments made based on their tolerability.
Q10: What should I advise patients regarding contraception while on Trabectedin?
A: Both male and female patients should use effective contraception during and after treatment due to the drug’s potential effects on fertility and potential harm to a developing fetus. Women should continue contraception for 3 months and men for 5 months after the last dose of Trabectedin.
