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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
UDNA
adduct
Humans
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
Adverseeffects
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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
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Lurbinectedin can be increased when it is combined with Abametapir.
AbirateroneThe serum concentration of Lurbinectedin can be increased when it is combined with Abiraterone.
AmiodaroneThe serum concentration of Lurbinectedin can be increased when it is combined with Amiodarone.
AmprenavirThe serum concentration of Lurbinectedin can be increased when it is combined with Amprenavir.
ApalutamideThe serum concentration of Lurbinectedin can be decreased when it is combined with Apalutamide.
AprepitantThe serum concentration of Lurbinectedin can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Lurbinectedin can be increased when it is combined with Atazanavir.
BerotralstatThe serum concentration of Lurbinectedin can be increased when it is combined with Berotralstat.
BexaroteneThe serum concentration of Lurbinectedin can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Lurbinectedin can be increased when it is combined with Boceprevir.
Interactions
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Food Interactions
No interactions found.

Products

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International/Other Brands
Zepsyre
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZepzelcaInjection, powder, lyophilized, for solution.5 mg/1mLIntravenousJazz Pharmaceuticals, Inc.2020-06-15Not applicableUS flag

Categories

Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]
  8. FDA Drug Approvals and Databases: FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer [Link]
PubChem Compound
57327016
PubChem Substance
347828878
ChemSpider
32701856
RxNav
2374729
ChEMBL
CHEMBL4297516
Wikipedia
Lurbinectedin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentOvarian Cancer1
3CompletedTreatmentSmall Cell Lung Cancer (SCLC)1
2Active Not RecruitingTreatmentSolid Tumors, Advanced Solid Tumors1
2CompletedOtherTumors, Solid1
2CompletedTreatmentBreast Cancer1
2CompletedTreatmentMetastatic Sarcoma1
2CompletedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2CompletedTreatmentPleural Mesothelioma Malignant Advanced1
1CompletedNot AvailableAcute Leukemia (Category)1
1CompletedTreatmentBreast Cancer / Gynecological Cancers / Head and Neck Carcinoma / Non Squamous Cell Lung Cancer / Non-Small Cell Lung Carcinoma (NSCLC) / Ovarian Cancer / Small Cell Lung Cancer (SCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7763615No2004-12-132024-12-13US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0646 mg/mLALOGPS
logP2.65ALOGPS
logP4.52ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)9.35ChemAxon
pKa (Strongest Basic)7.2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area164.28 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity205.9 m3·mol-1ChemAxon
Polarizability81.25 Å3ChemAxon
Number of Rings10ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Nucleotide
Organism
Humans
Pharmacological action
Unknown
Actions
Adduct
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
  1. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: Zepzelca (lurbinectedin) for intravenous injection [Link]

Drug created on October 20, 2016 23:34 / Updated on February 21, 2021 18:53