Identification

Name
Amrubicin
Accession Number
DB06263
Type
Small Molecule
Groups
Approved, Investigational
Description

Amrubicin is a third-generation synthetic anthracycline currently in development for the treatment of small cell lung cancer. Pharmion licensed the rights to Amrubicin in November 2006. In 2002, Amrubicin was approved and launched for sale in Japan based on Phase 2 efficacy data in both SCLC and NSCLC. Since January 2005, Amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical firm focused on oncology, which licensed Japanese marketing rights from Dainippon Sumitomo, the original developer of Amrubicin [13, 15].

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Amrubicin hydrochlorideEUL6MP8FZW110311-30-3BHMLHEQFWVQAJS-IITOGVPQSA-N
International/Other Brands
Calsed
Categories
UNII
93N13LB4Z2
CAS number
110267-81-7
Weight
Average: 483.473
Monoisotopic: 483.152931389
Chemical Formula
C25H25NO9
InChI Key
VJZITPJGSQKZMX-XDPRQOKASA-N
InChI
InChI=1S/C25H25NO9/c1-10(27)25(26)7-13-18(16(8-25)35-17-6-14(28)15(29)9-34-17)24(33)20-19(23(13)32)21(30)11-4-2-3-5-12(11)22(20)31/h2-5,14-17,28-29,32-33H,6-9,26H2,1H3/t14-,15+,16-,17-,25-/m0/s1
IUPAC Name
(7S,9S)-9-acetyl-9-amino-7-{[(2S,4S,5R)-4,5-dihydroxyoxan-2-yl]oxy}-6,11-dihydroxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione
SMILES
[H][C@@]1(C[C@@](N)(CC2=C1C(O)=C1C(=O)C3=CC=CC=C3C(=O)C1=C2O)C(C)=O)O[C@H]1C[C@H](O)[C@H](O)CO1

Pharmacology

Indication

Investigated for use/treatment in lung cancer [2].

Pharmacodynamics

The anthracycline glycoside group of antibiotics, which includes amrubicin, represent a group of potent anticancer agents with potent activity against both solid tumors and hematological malignancies. They are the principal subjects of a large number of studies for the treatment of adult and childhood neoplastic diseases [5].

Amrubicin is a 9-aminoanthracycline derivative and promotes cell growth inhibition by stabilizing protein – DNA complexes followed by double-stranded DNA breaks, which are mediated by topoisomerase-II enzyme [7].

Anthracyclines have been observed to have a variety molecular effects (for example, DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase IIα cleavable complexes). Amrubicin shows decreased DNA intercalation when compared with doxorubicin. The decreased DNA interaction likely influences the intracellular distribution because amrubicin and its metabolite, amrubicinol. Amrubicin showed 20% distribution into the nucleus of P388 cells compared with the 80% nuclear distribution shown by doxorubicin (another anthracycline drug). The cell growth inhibitory effects of amrubicin appear to be mainly due to the inhibition of topoisomerase II [11].

Mechanism of action

As an anthracycline, amrubicin has antimitotic and cytotoxic activity through a variety of mechanisms of action. Amrubicin is found to form complexes with DNA via intercalation between base pairs, and it inhibits topoisomerase II enzyme activity by stabilizing the DNA-topoisomerase II complex, which prevents the re-ligation portion of the ligation-religation reaction that topoisomerase II normally catalyzes [11].

Topoisomerase II is an enzyme located in the nucleus that regulates DNA structure through double-strand breakage and re-ligation, therefore modulating DNA replication and transcription. Inhibition of the enzyme leads to inhibition of DNA replication and halt cell growth with an arrest of the cell cycle occurring at the G2/M phase. The mechanism by which amrubicin inhibits DNA topoisomerase II is believed to be through stabilization of the cleavable DNA–topo II complex, ending in re-ligation failure and DNA strand breakage [11, 2].

DNA damage triggers activation of caspase-3 and -7 and cleavage of the enzyme PARP (Poly ADP ribose polymerase), leading to apoptosis and a loss of mitochondrial membrane potential. Amrubicin, like all anthracyclines, intercalates into DNA and produces reactive oxygen free radicals via interaction with NADPH, which causes cell damage [11].

Compared with doxorubicin, another member of the anthracycline drug class, amrubicin binds DNA with a 7-fold lower affinity and therefore, higher concentrations of amrubicin are necessary to promote DNA unwinding [11].

TargetActionsOrganism
UDNA topoisomerase 2-alphaNot AvailableHuman
UDNANot AvailableHuman
Absorption

Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after administration of amrubicin to 1h after administration. Plasma concentrations of amrubicinol were low compared with amrubicin plasma concentrations. The plasma amrubicinol AUC (area under the curve) was approximately 10-fold lower than the amrubicin plasma AUC. Concentrations of amrubicinol were higher in RBCs as compared with plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold higher in red blood cells (RBCs) compared to plasma. Because amrubicinol distributes itself into RBCs more than amrubicin, the concentrations of amrubicinol and amrubicin in RBCs were quite similar. The AUC of amrubicinol in RBCs was approximately twofold lower than the amrubicin RBC AUC [12].

In one study, after repeated daily amrubicin administration, amrubicinol accumulation was observed in plasma and RBCs. On day 3, the amrubicinol plasma AUC was 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 consecutive daily doses, plasma and RBC amrubicinol AUCs were 1.2-fold to 2.0-fold higher than day 1 values [12].

Volume of distribution

Moderate volume of distribution (1.4 times total body water) [11].

Protein binding

A study was performed on the plasma protein binding of amrubicin in both patients with hepatic impairment and those with normal liver function. In those with liver impairment, the plasma protein binding was found to be 91.3–97.1% and in those with normal hepatic function, 82.0–85.3% [12].

Metabolism

The primary metabolite (amrubicinol) in rats and dogs is a product of reduction by cytoplasmic carbonyl reductase at the C-13 carbonyl group. Other enzymes participating in the metabolism of amrubicin and amrubicinol were nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)–P450 reductase and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase. Twelve additional metabolites were detected in vivo and in vitro in one study [11].

Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after dosing to 1 hour after dosing [11].

These included four aglycone metabolites, two amrubicinol glucuronides, deaminated amrubicin, and five highly polar unknown metabolites. In vitro cell growth inhibitory activity of the minor metabolites was substantially lower than that of amrubicinol. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.

Route of elimination

In one study, urinary excretion of amrubicin and amrubicinol after ingestion of amrubicin accounted for 2.7% to 19.6% of the administered dose. The amount of excreted amrubicinol was approximately 10-fold greater than excreted amrubicin [11].

Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats [11].

Half life

20-30 h [6]

In a study of dogs, Amrubicin plasma concentrations followed a biphasic pattern with peak concentrations observed immediately after dosing followed by α and β half-lives (t1/2) ± SD of 0.06 ± 0.01 and 2.0 ± 0.3 hours, respectively [11].

Clearance

The plasma pharmacokinetics of amrubicin in cancer patients are characterized by low total clearance (22% of total liver blood flow) [11].

Toxicity

Based on acute intravenous dose toxicity studies, the lethal dose to 50% of animals was estimated to be 42 mg/kg in mice, 14 mg/kg in rats, and 4 mg/kg in dogs [11].

Myelosuppression, with the primary clinical manifestation of neutropenia and leucopenia, is the dose-limiting toxicity of this drug. In addition to this, mucositis, nausea, vomiting, and alopecia are frequent. Hepatopathy, observed with elevated bilirubin concentrations, occurs less frequently. Cardiotoxicity is a major adverse effect of the anthracycline antibiotics and may be acute or chronic; in the acute setting, electrocardiographic (ECG) abnormalities may be observed, demonstrating ST-T elevations and arrhythmias, however, chronic cardiotoxicity poses a serious risk that may be lethal due to the slow development of irreversible, cardiomyopathy. The occurrence of toxicity shows a significant interindividual variation, and for this reason, the pharmacokinetics and pharmacodynamics of anthracyclines have been heavily investigated in order to identify models that may be used in the clinical setting to prevent the development of serious toxicity, mainly leucopenia, and maximize tumor exposure [5]. Interestingly, a recent study was done to further examine genetic predisposition neutropenia/amrubicin toxicity. It was determined that C3435T polymorphisms of the ABCB1 gene might be able to predict severe amrubicin-induced neutropenia [9].

Secondary alcohol metabolites of earlier generation anthracyclines have been shown to lead to cardiac toxicity which is a major toxicity of conventional anthracyclines and thus limits the amount that can be delivered safely to patients. Clinical manifestations of toxicity observed on the acute and repeated administration of amrubicin in rats and dogs were dose-related and reversible including fecal changes (mucoid or bloody feces/diarrhea), body weight decreases, decreased food consumption, decreased activity, and alopecia. Similar findings were observed at doses of doxorubicin approximately one half those of amrubicin [11].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Amrubicin.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Amrubicin.Experimental
AncestimThe risk or severity of cytotoxicity can be increased when Ancestim is combined with Amrubicin.Approved, Investigational, Withdrawn
BevacizumabBevacizumab may increase the cardiotoxic activities of Amrubicin.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Amrubicin.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Amrubicin.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Amrubicin.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Amrubicin.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Amrubicin.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Amrubicin.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Amrubicin.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Amrubicin.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Amrubicin.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Amrubicin.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Amrubicin.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Amrubicin.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Amrubicin.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Amrubicin.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Amrubicin.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Amrubicin.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Amrubicin.Approved, Investigational
Food Interactions
Not Available

References

General References
  1. Katou M, Soga N, Onishi T, Arima K, Sugimura Y: Small cell carcinoma of the prostate treated with amrubicin. Int J Clin Oncol. 2008 Apr;13(2):169-72. doi: 10.1007/s10147-007-0702-x. Epub 2008 May 8. [PubMed:18463964]
  2. Kurata T, Okamoto I, Tamura K, Fukuoka M: Amrubicin for non-small-cell lung cancer and small-cell lung cancer. Invest New Drugs. 2007 Oct;25(5):499-504. Epub 2007 Jul 13. [PubMed:17628745]
  3. Tani N, Yabuki M, Komuro S, Kanamaru H: Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride. Xenobiotica. 2005 Dec;35(12):1121-33. doi: 10.1080/00498250500342746 . [PubMed:16418065]
  4. Ettinger DS: Amrubicin for the treatment of small cell lung cancer: does effectiveness cross the Pacific? J Thorac Oncol. 2007 Feb;2(2):160-5. doi: /JTO.0b013e31802f1cd9. [PubMed:17410034]
  5. Danesi R, Fogli S, Gennari A, Conte P, Del Tacca M: Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokinet. 2002;41(6):431-44. doi: 10.2165/00003088-200241060-00004. [PubMed:12074691]
  6. Eksborg S: Pharmacokinetics of anthracyclines. Acta Oncol. 1989;28(6):873-6. [PubMed:2611038]
  7. Hanada M, Mizuno S, Fukushima A, Saito Y, Noguchi T, Yamaoka T: A new antitumor agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex. Jpn J Cancer Res. 1998 Nov;89(11):1229-38. [PubMed:9914793]
  8. Hira A, Watanabe H, Maeda Y, Yokoo K, Sanematsu E, Fujii J, Sasaki J, Hamada A, Saito H: Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells. Biochem Pharmacol. 2008 Feb 15;75(4):973-80. doi: 10.1016/j.bcp.2007.10.023. Epub 2007 Oct 30. [PubMed:18054347]
  9. Takakuwa O, Oguri T, Uemura T, Kunii E, Nakao M, Hijikata H, Kawaguchi Y, Ohkubo H, Takemura M, Maeno K, Niimi A: ABCB1 polymorphism as a predictive biomarker for amrubicin-induced neutropenia. Anticancer Res. 2014 Jul;34(7):3517-22. [PubMed:24982363]
  10. Amrubicin [Link]
  11. Amrubicin for the Treatment of Small Cell Lung Cancer: Does Effectiveness Cross the Pacific? [Link]
  12. Pharmacokinetics of amrubicin in lung cancer patients with impaired hepatic function [Link]
  13. Amrubicin® Receives FDA Orphan Drug Designation for the Treatment of Small Cell Lung Cancer [Link]
  14. Phase I–II study of amrubicin and cisplatin in previously untreated patients with extensive-stage small-cell lung cancer [Link]
  15. randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer [Link]
External Links
PubChem Compound
3035016
PubChem Substance
347827767
ChemSpider
2299344
ChEBI
135779
ChEMBL
CHEMBL1186894
Wikipedia
Amrubicin
ATC Codes
L01DB10 — Amrubicin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Solid Tumors1
1CompletedTreatmentLung Cancers2
1, 2CompletedTreatmentMetastatic Breast Cancer (MBC)1
1, 2CompletedTreatmentMultiple Myeloma (MM)1
2Active Not RecruitingOtherAdvanced thymic carcinoma / Thymic Carcinoma / Thymus Cancer1
2CompletedTreatmentExtensive-Stage Small Cell Lung Cancer1
2CompletedTreatmentLung Cancer Small Cell Lung Cancer (SCLC)3
2CompletedTreatmentSoft Tissue Sarcoma (STS)1
2RecruitingTreatmentSmall Cell Lung Cancer Extensive Stage1
2TerminatedTreatmentBladder Cancers1
2TerminatedTreatmentLung Cancer Small Cell Lung Cancer (SCLC)1
2WithdrawnTreatmentMetastatic Breast Cancer (MBC)1
3Active Not RecruitingTreatmentLung Cancers1
3CompletedTreatmentLung Cancer Small Cell Lung Cancer (SCLC)1
3CompletedTreatmentLung Cancers1
3TerminatedTreatmentLung Cancer Small Cell Lung Cancer (SCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)172-174 http://www.lookchem.com/Amrubicin/
boiling point (°C)717.8http://www.lookchem.com/Amrubicin/
water solubilitynot soluble in water, but soluble in DMSOhttps://medkoo.com/products/5056
logP2.64http://www.lookchem.com/Amrubicin/
Predicted Properties
PropertyValueSource
Water Solubility1.14 mg/mLALOGPS
logP1.4ALOGPS
logP1.74ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)8.1ChemAxon
pKa (Strongest Basic)7.02ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area176.61 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity122.01 m3·mol-1ChemAxon
Polarizability48.75 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as tetracenequinones. These are polyaromatic hydrocarbon derivatives containing a tetracyclic cycle made up of four linearly fused benzene rings, one of which bears two ketone groups at position 1 and 4.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Naphthacenes
Sub Class
Tetracenequinones
Direct Parent
Tetracenequinones
Alternative Parents
Anthraquinones / O-glycosyl compounds / Tetralins / Aryl ketones / Aralkylamines / Oxanes / Vinylogous acids / Alpha-amino ketones / Secondary alcohols / 1,2-diols
show 6 more
Substituents
Tetracenequinone / 9,10-anthraquinone / 1,4-anthraquinone / Anthracene / Glycosyl compound / O-glycosyl compound / Tetralin / Aryl ketone / Aralkylamine / Oxane
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Ubiquitin binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segr...
Gene Name
TOP2A
Uniprot ID
P11388
Uniprot Name
DNA topoisomerase 2-alpha
Molecular Weight
174383.88 Da
References
  1. Kurata T, Okamoto I, Tamura K, Fukuoka M: Amrubicin for non-small-cell lung cancer and small-cell lung cancer. Invest New Drugs. 2007 Oct;25(5):499-504. Epub 2007 Jul 13. [PubMed:17628745]
2. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Unknown
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, nad(p)h as one donor, and incorporation of one atom of oxygen
Specific Function
This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.
Gene Name
POR
Uniprot ID
P16435
Uniprot Name
NADPH--cytochrome P450 reductase
Molecular Weight
76689.12 Da
References
  1. Tani N, Yabuki M, Komuro S, Kanamaru H: Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride. Xenobiotica. 2005 Dec;35(12):1121-33. doi: 10.1080/00498250500342746 . [PubMed:16418065]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Prostaglandin-e2 9-reductase activity
Specific Function
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. ...
Gene Name
CBR1
Uniprot ID
P16152
Uniprot Name
Carbonyl reductase [NADPH] 1
Molecular Weight
30374.73 Da
References
  1. Tani N, Yabuki M, Komuro S, Kanamaru H: Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride. Xenobiotica. 2005 Dec;35(12):1121-33. doi: 10.1080/00498250500342746 . [PubMed:16418065]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da
References
  1. Hira A, Watanabe H, Maeda Y, Yokoo K, Sanematsu E, Fujii J, Sasaki J, Hamada A, Saito H: Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells. Biochem Pharmacol. 2008 Feb 15;75(4):973-80. doi: 10.1016/j.bcp.2007.10.023. Epub 2007 Oct 30. [PubMed:18054347]

Drug created on March 19, 2008 10:20 / Updated on June 02, 2018 09:45