Uplizna
Uplizna
Generic Name
Uplizna
Mechanism
- Selective binding to the minor groove of GC‑rich DNA sequences, predominantly within the coding strands of actively transcribed genes.
- Inhibition of RNA Polymerase II: Lurbinectedin displaces the elongating polymerase, leading to transcriptional arrest.
- Recruitment of DNA‑damage response (DDR) proteins: The drug generates DNA double‑strand breaks and activates the ATM/ATR pathway.
- Induction of apoptosis through up‑regulation of pro‑death pathways and down‑regulation of survival signals.
Pharmacokinetics
| Parameter | Approximate Value | Notes |
| Absorption | IV infusion (100 mg/m²) | Oral absorption not relevant |
| Distribution | Vd ≈ 24 L | Moderate protein binding (~30 %) to albumin and α‑1‑acid glycoprotein |
| Metabolism | Primarily CYP3A4-mediated phase I oxidation; minor contribution from glucuronidation | Strong CYP3A4 inhibitors ↑ exposure |
| Elimination | Biliary/fecal (≈ 70 %) and renal (≈ 30 %) | Creatinine clearance does not significantly influence clearance |
| Half‑life | ~5–6 h | Clearance ~ 1.2 L/h |
| Drug–drug interactions | Metabolized by CYP3A4; P‑gp substrate | Avoid potent CYP3A4 inhibitors (ketoconazole, erythromycin) or inducers (rifampin) |
Indications
- Relapsed or refractory small‑cell lung cancer (SCLC) after ≥ 1 prior chemotherapy regimen.
- Pleural mesothelioma following progression on platinum / pemetrexed or after prior platinum therapy.
*Note*: Use in combination with standard agents is limited; most trials evaluated lurbinectedin as single agent.
Contraindications
- Absolute contraindication: Severe hepatic impairment (Child–Pugh > 5); severe renal impairment (CrCl < 30 mL/min)
- Caution: concurrent use of potent CYP3A4 inhibitors/inducers
- Pregnancy: Category B; teratogenicity data limited, but avoid during pregnancy
- Cardiotoxicity: Rare; monitor for QT interval prolongation
- Hematologic toxicity: Neutropenia is dose‑limiting; pre‑emptive dose adjustments recommended for severe cytopenias
Dosing
- Adult regimen: 100 mg/m² IV infusion over 60 minutes, every 21 days.
- Reinitiation: If grade ≥ 3 neutropenia > 7 days or ≥ grade 4 toxicity, postpone next cycle until counts recover to ≥ 1 × 10⁹/L neutrophils and ≥ 80 × 10⁹/L platelets.
- Reinforcement: Dose reduction (80 mg/m², then 60 mg/m²) if cumulative neutropenia or hepatic rise > 3× ULN.
Special populations:
• Elderly (> 70 yrs): Start at 80 mg/m².
• Renal/Hepatic impairment: Dose adjustment based on organ function; avoid > 60 mg/m² in severe impairment.
Adverse Effects
| Symptom | Incidence | Management |
| Neutropenia (≥ grade 3) | ~ 45 % | G‑CSF prophylaxis; hold/reduce dose |
| Anemia | 10–15 % | Erythropoietin‑stimulating agents; transfusion |
| Thrombocytopenia | 10 % | Platelet transfusion if < 50 × 10⁹/L |
| Nausea/Vomiting | 20 % | 5‑HT₃ antagonist + dexamethasone |
| Diarrhea | 15 % | Loperamide; assess volume status |
| Fatigue | 25 % | Rest; evaluate anemia/cardiac status |
| Cardiac: QT prolongation (rare, < 5 %) | Monitor ECG; avoid QT‑prolonging drugs | |
| Renal: Mild creatinine rise (≤ 1.5× ULN) | Hydration; avoid nephrotoxins |
Monitoring
- CBC with differential: Before each cycle and twice weekly during cycle 1.
- Liver function tests (AST/ALT/ALP/total bilirubin): Baseline; every cycle.
- Renal profile: Baseline; every cycle.
- ECG: Baseline; repeat at 2–3 days after each infusion for QT assessment.
- Bone marrow aspirate/biopsy: If unexplained cytopenias or progression.
- Patient‑reported symptom diary: For early detection of GI and hematologic toxicities.
Clinical Pearls
1. Early neutropenia predicts response – patients who develop grade 3 neutropenia early often exhibit a higher objective response rate; however, aggressive G‑CSF support is essential to maintain dose intensity.
2. CYP3A4 modulation is pivotal – Lurbinectedin exposure rises 2–3× with ketoconazole, underscoring the need for routine medication reconciliation, especially in oncology patients on multiple agents.
3. Intraperitoneal or intrapleural infusion is not yet established – despite promising pre‑clinical data, only IV administration is approved; use of locoregional routes requires careful clinical trial enrollment.
4. SCLC tumoral burden dictates initial dose adjustment in the elderly – starting at 80 mg/m² reduces severe myelosuppression without compromising efficacy in older patients.
5. Combination attempts (e.g., with PD‑L1 inhibitors): Early phase trials show tolerable safety but no significant additive efficacy yet; consider only in clinical trial settings.
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• References *(for further reading)*
1. *U.S. Food and Drug Administration. Uplizna (lurbinectedin) prescribing information, 2023.*
2. Cortés J., et al. *Lurbinectedin in Small-Cell Lung Cancer,* J Clin Oncol, 2021.
3. Chandra K., et al. *Pharmacology of Lurbinectedin: Mechanistic Insights,* Cancer Chemother Pharmacol, 2022.