What Is Lurbinectedin (Zepzelca)? FDA Approval, Licensing in Turkey, and Reimbursement Status

• FDA Approved: Yes (Initial approval date: June 15, 2020)
• Product Name (Brand Name): Zepzelca®
• Active Ingredient: Lurbinectedin
• Route of Administration: Intravenous infusion (into a vein)
• Drug Class: Transcription inhibitor – alkaloid-derived antineoplastic agent
• Category: Antineoplastic (an agent used to treat cancer)
• Manufacturer: Jazz Pharmaceuticals / PharmaMar
• Distribution in Turkey: Currently not licensed in Turkey.
• Cancer Type for Which It Is Approved: Metastatic small cell lung cancer (SCLC)

What Is Lurbinectedin?

Lurbinectedin (Zepzelca) is a chemotherapy drug that targets and stops the genetic processes that enable cancer cells to grow and multiply.

A brief history of the discovery of lurbinectedin (Zepzelca) from marine organisms:

• 1980s: Scientists discovered a natural compound in a sea squirt called Ecteinascidia turbinata. The compound, ecteinascidin 743 (ET-743), was found to have potent effects on cancer cells.

• 1990s: The Spanish biotechnology company PharmaMar began producing ET-743 synthetically, and the compound was named trabectedin (Yondelis).

• 2000s: Trabectedin received approval for certain cancers, including soft tissue sarcomas and ovarian cancer. However, researchers continued working to develop a more effective derivative with fewer side effects.

• 2010s: A new compound called lurbinectedin (PM1183) was synthesized. Like trabectedin, it worked by binding to DNA, but it had a more potent effect.

• 2020: Lurbinectedin received accelerated approval from the US Food and Drug Administration (FDA) for small cell lung cancer (SCLC) and was marketed under the brand name Zepzelca.

Mechanism of Action

Lurbinectedin targets specific regions of DNA and prevents proteins from binding at these sites, thereby stopping oncogenic transcription. It degrades RNA polymerase II to prevent genetic information from being copied, causes double-strand DNA breaks, and triggers apoptosis (programmed cell death).

FDA Approval History

• June 15, 2020: Received FDA approval for the treatment of metastatic small cell lung cancer. Source

Licensing Status in Turkey

It is currently not licensed in Turkey. However, it may be included on the overseas medicines list and obtained by special authorization with approval from the Turkish Medicines and Medical Devices Agency (TİTCK).

Reimbursement Status

Because it is not licensed in Turkey, it is not reimbursed by the Social Security Institution (SGK).

• Price: Although Zepzelca is not available in Turkey, its 4 mgintravenous powder for injection is listed at a US price of 8,476.09 dollars per product.

Mechanisms of Resistance

• Increased DNA repair pathways: In particular, increased NER (nucleotide excision repair) activity may cause resistance to the drug.
• Increased efflux pumps: Structures such as P-glycoprotein cause the drug to be expelled from the cell.
• Transcriptional adaptation: Resistance to the drug can develop through alternative genetic pathways.
• Increased CYP3A4 activity: Rapid metabolism of the drug may reduce its effect.

Pharmacokinetic Properties

• Absorption: 100% bioavailability with IV infusion.
• Distribution: 99% binds to plasma proteins. Volume of distribution ≈ 500 L.
• Metabolism: Metabolized in the liver by the CYP3A4 enzyme.
• Excretion: 89% in feces and 6% in urine. The elimination half-life is approximately 51 hours.

Dosage and Administration

• Recommended dose: 2.6 mg/m²
• Administration: Given every 21 days as an IV infusion lasting approximately 1 hour.
• Duration of treatment: Continued until progression or unacceptable toxicity.

Drug Interactions

• CYP3A4 inhibitors: Ketoconazole, itraconazole, clarithromycin, grapefruit juice
• CYP3A4 inducers: Rifampin, phenytoin, carbamazepine, St. John's wort
• Supportive treatments: Caution is needed when used with agents that suppress bone marrow.

Precautions

• Drugs such as ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole may decrease lurbinectedin metabolism, leading to increased drug levels and potential toxicity.
• Drugs such as rifampin, phenytoin, phenobarbital, carbamazepine, and St. John's wort may increase lurbinectedin metabolism, leading to inactivation of the drug and lower effective drug levels.
• Dose reduction is not recommended in patients with mild hepatic impairment. It has not been studied in moderate or severe hepatic impairment.
• Dose reduction is not necessary in patients with mild or moderate renal impairment. It has not been studied in severe renal impairment or end-stage renal disease.
• Complete blood counts should be monitored periodically, especially white blood cells and the absolute neutrophil count.
• Liver function tests (LFTs) should be monitored periodically during treatment. The median time to onset of abnormal LFTs is 8 days, and their median duration is 7 days.
• Patients should be monitored for signs and symptoms of an extravasation reaction during infusion. A central venous catheter should be used to administer the drug.
• Creatine phosphokinase (CPK) levels should be monitored at baseline and periodically during treatment.
• It may harm the fetus when administered to a pregnant woman. Women of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose. Breastfeeding is not recommended.

Side Effects

The most common side effects:

• Anemia: 96%
• Leukopenia: 72%
• Fatigue: 58%
• Thrombocytopenia: 44%
• Nausea: 32%
• Loss of appetite: 21%
• Vomiting: 18%
• Diarrhea: 15%
• Febrile neutropenia: 5%
• Elevated liver enzymes: 5%
• Pneumonia: 2%
• Skin ulcer: 1%

Treatment discontinuation rate: 2% of patients discontinue treatment because of side effects.