Yondelis
Yondelis
Generic Name
Yondelis
Mechanism
- Yondelis (trabectedin) is a marine‑derived alkaloid that binds the minor groove of DNA within the G‑C rich AT blocks.
- This DNA‑ligand interaction distorts the helix, interfering with transcription, RNA polymerase II elongation, and DNA repair mechanisms.
- By disrupting NAB (Nucleosome-associated factors) and p53‑dependent signaling, Yondelis triggers a cascade that leads to apoptosis in chemosensitive cells.
- The drug is especially potent against tumor‑infiltrating monocytes/macrophages, thereby diminishing the tumor‑promoting inflammatory microenvironment.
Pharmacokinetics
| Parameter | Typical Value |
| Absorption | Intravenous administration only; negligible oral bioavailability. |
| Distribution | 90–95 % plasma protein binding (primarily albumin); volume of distribution ≈ 18 L⁻¹. |
| Metabolism | Primarily via CYP3A4 in the liver; minor CYP1A2/1B1 contribution. |
| Excretion | 60–70 % biliary; 20–30 % renal (glucuronidated conjugates). |
| Half‑life | ~20–25 h in healthy volunteers; prolonged in hepatic impairment. |
| Special populations | Patients with hepatic impairment show a 1.5‑2‑fold increase in AUC; no dose adjustment required for renal impairment. |
Indications
- Soft‑tissue sarcoma (STS) – refractory or progressed after anthracycline‑based therapy.
- Advanced or metastatic leiomyosarcoma – following failure of standard chemotherapy.
- Treatment‑naïve patients: Yondelis can be considered in first‑line regimens for selected high‑risk STS subtypes (e.g., alveolar soft part sarcoma).
- Combination regimens (e.g., Yondelis + dacarbazine for STS; or Yondelis + trabectedin in AML) are under investigation but not yet FDA‑approved.
Contraindications
- Absolute contraindications: Hypersensitivity to Yondelis, its excipients, or to other agents in the same class.
- Relative contraindications:
- Severe hepatic impairment (Child‑Pugh C).
- Significant thrombocytopenia (< 70 × 10⁹/L) or neutropenia (< 1 × 10⁹/L) prior to initiation.
- Warnings:
- Myelosuppression (dose‑limiting toxicity); schedule 3 mg/m² IV every 3 weeks.
- Peripheral neuropathy – mild to moderate; dose modification may be required.
- Cardiotoxicity – rare but documented in patients with pre‑existing arrhythmias or left ventricular dysfunction.
- Potential for severe hypersensitivity reactions, requiring pre‑medication and emergency protocols.
- Drug‑Drug Interactions:
- Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure → dose reduction.
- Strong CYP3A4 inducers (rifampin, carbamazepine) decrease efficacy → consider therapeutic monitoring.
Dosing
- Adult: 3 mg/m² IV infusion over 60 min every 3 weeks (Cohort 1).
- Alternative Schedule: 1.5 mg/m² IV weekly for 8 weeks (Cohort 2) – may reduce cumulative myelosuppression.
- Infusion precautions: Pre‑medicate with acetaminophen and antihistamine if hypersensitivity suspected.
- Special instructions:
- Monitor cardiac baseline (ECG) before first cycle; repeat after 2 cycles if symptomatic.
- Use colony‑stimulating factors only if neutropenia ≥ Grade 3.
- Maintain adequate hydration (10–20 mL/kg IV) during infusion to mitigate renal damage.
Adverse Effects
- Common (≥ 30 %):
- Myelosuppression: anemia, neutropenia, thrombocytopenia.
- Gastrointestinal: nausea, vomiting, diarrhea.
- Fluid retention, mild peripheral neuropathy.
- Serious (≥ 5 %):
- Grade 4 neutropenia → febrile neutropenia.
- Cardiac arrhythmias (QT prolongation).
- Severe hypersensitivity (anaphylaxis).
- Rare: Hepatic transaminase elevation > 5× ULN, interstitial lung disease.
Monitoring
| Parameter | Frequency | Action |
| CBC with differential | Prior to each infusion | Hold dose if neutrophils < 1 × 10⁹/L; treat febrile neutropenia promptly |
| Platelets | Prior to each infusion | Hold dose if 5× ULN |
| ECG | Baseline, week 3, and at any cardiac symptoms | Monitor QTc; discontinue if > 500 ms |
| Neuropathy assessment | Every visit | Document severity; consider dose reduction/stop if Grade 3+ |
Clinical Pearls
- Bidirectional metabolic support: Because trabectedin is metabolized by CYP3A4, avoid concomitant ketoconazole, clarithromycin, or other strong inhibitors; conversely, rifampin can ablate efficacy.
- Platelets are a sentinel marker: Early thrombocytopenia predicts eventual myelosuppression; intensive monitoring can pre‑empt severe cytopenias.
- Combination advantage: Pairing Yondelis with dacarbazine in soft‑tissue sarcomas may exploit synergistic DNA damage pathways; however, it amplifies myelosuppression—dose‑leveling is critical.
- Elderly patients: Age > 70 doesn’t necessitate dose reduction, but intensity of monitoring should be increased due to comorbidities.
- Hepatic impairment: For Child‑Pugh B, reduce dose to 2 mg/m²; avoid use in Child‑Pugh C.
- Patient education: Since Yondelis is an infusion drug, patients should wear “myelosuppression alert” bracelets and be advised to report fevers or signs of infection immediately.
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• *All information is current as of June 2024 and is intended for educational purposes only. Always consult up‑to‑date prescribing information and institutional guidelines prior to therapy.*