Lurbinectedin
Identification
- Summary
Lurbinectedin is a chemotherapeutic DNA alkylating agent used in the treatment of metastatic small-cell lung cancer.
- Brand Names
- Zepzelca
- Generic Name
- Lurbinectedin
- DrugBank Accession Number
- DB12674
- Background
Lurbinectedin is a DNA alkylating agent that has been investigated in the treatment of a variety of cancers, including mesothelioma,4 chronic lymphocytic leukemia (CLL),5 breast cancer,3 and small-cell lung cancer (SCLC).1 It is a derivative of the marine-derived agent ecteinascidin (trabectedin), an anticancer agent found in extracts of the tunicate Ecteinascidia turbinata, with the primary difference being the substitution of the tetrahydroisoquinoline with a tetrahydro β‐carboline that results in increased antitumour activity of lurbinectedin as compared to its predecessor.6
On June 15, 2020, the FDA granted accelerated approval and orphan drug designation to lurbinectedin for the treatment of adult patients with metastatic SCLC who have experienced disease progression despite therapy with platinum-based agents.8 This accelerated approval is based on the rate and duration of therapeutic response observed in ongoing clinical trials and is contingent on the verification of these results in confirmatory trials.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 784.88
Monoisotopic: 784.277814807 - Chemical Formula
- C41H44N4O10S
- Synonyms
- Lurbinectedin
- External IDs
- PM 01183
- PM-01183
- PM01183
- PM1183
- WHO 9397
Pharmacology
- Indication
Lurbinectedin is indicated for the treatment of adult patients with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Metastatic small cell lung cancer •••••••••••• ••••• ••••••• ••••••••••• •• •• ••••• •••••••••••••• •••••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Lurbinectedin exerts its chemotherapeutic activity by covalently binding to DNA, resulting in double-strand DNA breaks and subsequent cell death.1 Lurbinectedin has been associated with myelosuppression, and patients receiving therapy with this agent should be closely monitored for evidence of cytopenias. Prior to beginning therapy, ensure baseline neutrophil counts are >1,500 cells/mm3 and platelet counts are >100,000/mm3.7 The supplementary use of granulocyte colony-stimulating factor (G-CSF) should be considered if the neutrophil count falls below 500 cells/mm3.7 Lurbinectedin has also been associated with hepatotoxicity.7 Monitor liver function tests at baseline and regular intervals throughout therapy, and consider holding, reducing, or permanently discontinuing therapy based on the severity of observed hepatotoxicity.7
- Mechanism of action
Lurbinectedin is a DNA alkylating agent.7 It covalently binds to guanine residues in the DNA minor groove, forming adducts that bend the DNA helix towards the major groove. This process triggers a cascade of events that affect the activity of transcription factors and impairs DNA repair pathways, ultimately leading to double-strand DNA breaks and eventual cell death.7,1 Additional mechanism(s) of action include inhibition of RNA-polymerase-II activity, inactivation of Ewing Sarcoma Oncoprotein (EWS-FL11) via nuclear redistribution, and the inhibition of human monocyte activity and macrophage infiltration into tumor tissue.7,1
Target Actions Organism UDNA adductHumans - Absorption
Following intravenous administration, the Cmax and AUC0-inf were 107 µg/L and 551 µg*h/L, respectively. No accumulation between dosing intervals (every 3 weeks) has been observed.7 No significant differences in absorption were found between special populations (e.g. based on age, sex, ethnicity, etc.), but lurbinectedin has not been studied in the setting of severe renal impairment or moderate/severe hepatic impairment.
- Volume of distribution
The steady-state volume of distribution of lurbinectedin is 504 L.7
- Protein binding
Lurbinectedin is highly protein-bound in plasma (~99%) to both serum albumin and α-1-acid glycoprotein.7
- Metabolism
Lurbinectedin is metabolized primarily by CYP3A4 in vitro, though specific data regarding its biotransformation are lacking.7 An N-desmethylated metabolite has been identified in canine subjects.2
- Route of elimination
Approximately 89% of a given dose is recovered in the feces (<0.2% unchanged) and 6% in the urine (1% unchanged).7
- Half-life
The terminal half-life of lurbinectedin is 51 hours.7
- Clearance
The total plasma clearance of lurbinectedin is approximately 11 L/h.7
- Adverse Effects
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- Toxicity
Data regarding overdosage with lurbinectedin are not available. Symptoms of overdose are likely to be consistent with lurbinectedin's adverse effect profile.7
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Lurbinectedin can be increased when it is combined with Abametapir. Ambroxol The risk or severity of methemoglobinemia can be increased when Lurbinectedin is combined with Ambroxol. Amiodarone The serum concentration of Lurbinectedin can be increased when it is combined with Amiodarone. Amprenavir The serum concentration of Lurbinectedin can be increased when it is combined with Amprenavir. Apalutamide The serum concentration of Lurbinectedin can be decreased when it is combined with Apalutamide. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Zepsyre
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zepzelca Powder 4 mg / vial Intravenous Jazz Pharmaceuticals Ireland Limited 2021-12-06 Not applicable Canada Zepzelca Injection, powder, lyophilized, for solution .5 mg/1mL Intravenous Jazz Pharmaceuticals, Inc. 2020-06-15 Not applicable US
Categories
- ATC Codes
- L01XX69 — Lurbinectedin
- Drug Categories
- Alkylating Drugs
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Indole Alkaloids
- Indoles
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- OCT1 inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Pyridines
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as harmala alkaloids. These are compounds with a structure based on harmaline, harmine, harmalol, harman or a derivative of those parents. These parents are beta-carbolines, consisting of a pyrimidine fused to the pyrrole moiety of an indole to form a pyrido[3,4-b]indole.
- Kingdom
- Organic compounds
- Super Class
- Alkaloids and derivatives
- Class
- Harmala alkaloids
- Sub Class
- Not Available
- Direct Parent
- Harmala alkaloids
- Alternative Parents
- Beta carbolines / Benzazocines / Tetrahydroisoquinolines / 3-alkylindoles / Alpha amino acids and derivatives / Benzodioxoles / Anisoles / 1-hydroxy-4-unsubstituted benzenoids / Alkyl aryl ethers / N-methylpiperazines show 17 more
- Substituents
- 1,4-diazinane / 1-hydroxy-4-unsubstituted benzenoid / 3-alkylindole / Acetal / Alkanolamine / Alkyl aryl ether / Alpha-amino acid or derivatives / Amine / Amino acid or derivatives / Anisole show 39 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 2CN60TN6ZS
- CAS number
- 497871-47-3
- InChI Key
- YDDMIZRDDREKEP-HWTBNCOESA-N
- InChI
- InChI=1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1
- IUPAC Name
- (1R,2R,3R,11S,12S,14R,26R)-5,12-dihydroxy-6,6'-dimethoxy-7,21,30-trimethyl-27-oxo-2',3',4',9'-tetrahydro-17,19,28-trioxa-24-thia-13,30-diazaspiro[heptacyclo[12.9.6.1^{3,11}.0^{2,13}.0^{4,9}.0^{15,23}.0^{16,20}]triacontane-26,1'-pyrido[3,4-b]indole]-4,6,8,15,20,22-hexaen-22-yl acetate
- SMILES
- [H][C@@]12[C@@H]3SC[C@]4(NCCC5=C4NC4=CC=C(OC)C=C54)C(=O)OC[C@H](N1[C@@H](O)[C@@H]1CC4=CC(C)=C(OC)C(O)=C4[C@@]2([H])N1C)C1=C2OCOC2=C(C)C(OC(C)=O)=C31
References
- Synthesis Reference
He W, Zhang Z, Ma D: A Scalable Total Synthesis of the Antitumor Agents Et-743 and Lurbinectedin. Angew Chem Int Ed Engl. 2019 Mar 18;58(12):3972-3975. doi: 10.1002/anie.201900035. Epub 2019 Feb 14.
- General References
- Kauffmann-Guerrero D, Huber RM: Orphan Drugs in Development for the Treatment of Small-Cell Lung Cancer: Emerging Data on Lurbinectedin. Lung Cancer (Auckl). 2020 Mar 2;11:27-31. doi: 10.2147/LCTT.S239223. eCollection 2020. [Article]
- Altares R, Marquez Del Pino FM, Benedit G, Guillen MJ, Cuevas C, Perez de la Cruz MA, Aviles P: Development of a new method for the quantitation of metabolites in the absence of chemically synthetized authentic standards. J Pharm Biomed Anal. 2019 May 30;169:70-74. doi: 10.1016/j.jpba.2019.01.027. Epub 2019 Feb 21. [Article]
- Gourd E: Lurbinectedin for BRCA-mutated advanced breast cancer. Lancet Oncol. 2018 Nov;19(11):e582. doi: 10.1016/S1470-2045(18)30737-X. Epub 2018 Sep 27. [Article]
- Metaxas Y, Fruh M, Eboulet EI, Grosso F, Pless M, Zucali PA, Ceresoli GL, Mark M, Schneider M, Maconi A, Perrino M, Biaggi-Rudolf C, Froesch P, Schmid S, Waibel C, Appenzeller C, Rauch D, von Moos R: Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16). Ann Oncol. 2020 Apr;31(4):495-500. doi: 10.1016/j.annonc.2019.12.009. Epub 2020 Jan 16. [Article]
- Risnik D, Colado A, Podaza E, Almejun MB, Elias EE, Bezares RF, Fernandez-Grecco H, Seija N, Oppezzo P, Borge M, Gamberale R, Giordano M: Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia. Cancer Immunol Immunother. 2020 May;69(5):813-824. doi: 10.1007/s00262-020-02513-y. Epub 2020 Feb 13. [Article]
- Jimenez PC, Wilke DV, Branco PC, Bauermeister A, Rezende-Teixeira P, Gaudencio SP, Costa-Lotufo LV: Enriching cancer pharmacology with drugs of marine origin. Br J Pharmacol. 2020 Jan;177(1):3-27. doi: 10.1111/bph.14876. Epub 2019 Dec 23. [Article]
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
- FDA Drug Approvals and Databases: FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer [Link]
- External Links
- PubChem Compound
- 57327016
- PubChem Substance
- 347828878
- ChemSpider
- 32701856
- 2374729
- ChEMBL
- CHEMBL4297516
- Wikipedia
- Lurbinectedin
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Small Cell Lung Cancer (SCLC) 1 3 Completed Treatment Ovarian Cancer 1 3 Completed Treatment Small Cell Lung Cancer (SCLC) 1 3 Not Yet Recruiting Treatment Small Cell Lung Cancer (SCLC) 1 3 Recruiting Treatment Relapsed Small Cell Lung Cancer (SCLC) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, lyophilized, for solution Intravenous .5 mg/1mL Powder Intravenous 4 mg / vial Injection, powder, lyophilized, for solution Intravenous 4.0 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7763615 No 2010-07-27 2024-12-13 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0646 mg/mL ALOGPS logP 2.65 ALOGPS logP 4.52 Chemaxon logS -4.1 ALOGPS pKa (Strongest Acidic) 9.35 Chemaxon pKa (Strongest Basic) 7.2 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 11 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 164.28 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 205.9 m3·mol-1 Chemaxon Polarizability 81.25 Å3 Chemaxon Number of Rings 10 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 273.2524055 predictedDarkChem Lite v0.1.0 [M-H]- 271.73566 predictedDeepCCS 1.0 (2019) [M+H]+ 271.6111055 predictedDarkChem Lite v0.1.0 [M+H]+ 273.45938 predictedDeepCCS 1.0 (2019) [M+Na]+ 273.7857055 predictedDarkChem Lite v0.1.0 [M+Na]+ 279.7883 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Not Available
- Specific Function
- Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23511.38 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Secondary active organic cation transmembrane transporter activity
- Specific Function
- Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
- Gene Name
- SLC22A1
- Uniprot ID
- O15245
- Uniprot Name
- Solute carrier family 22 member 1
- Molecular Weight
- 61153.345 Da
References
- FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
Drug created at October 20, 2016 23:34 / Updated at February 20, 2024 23:54