Pixantrone

Identification

Name
Pixantrone
Accession Number
DB06193
Type
Small Molecule
Groups
Approved, Investigational
Description

Pixantrone is an aza-anthracenedione and DNA intercalator which inhibits topoisomerase II. It is similar in structure to anthracyclines such as mitoxantrone, but exerts fewer toxic effects on cardiac tissue. [2] The lower cardio-toxic effects of pixantrone may be explained, in part, by its redox inactivity [3]. Pixantrone does not bind iron and promotes the formation of reactive oxygen species to a lesser degree than other anthracyclines. It also inhibits doxorubicinol formation in human myocardium. [3] As a result, it is believed to be less cardiotoxic while still exerting efficacy.

Pixantrone was designed to treat relapsed or refractory aggressive non-Hodgkin's lymphoma(NHL) in patients who have failed two prior lines of therapy. [2] For patients suffering from NHL, first line therapies consist of anthracycline containing multi-drug treatments which unfortunately are known to cause irreversible myocardial tissue damage. Patients refractory to treatment, or those who relapse, are discouraged from further anthracycline use due to cumulative cardiotoxicity. Pixantrone dimaleate, administered intravenously, was designed by Cell Therapeutics Incorporated as an alternative second line therapy in refractory or relapsed NHL. It is currently being tested in Phase III trials. [2]

Although pixantrone has not yet received FDA approval in the United States, it has been granted conditional marketing approval by the European Union. Conditional approval was granted by the European Medicines Agency after a phase III EXTEND trial of patients with NHL showed that pixantrone was tolerable and that it resulted in significantly higher complete response rate and progression free survival in comparison to other single chemotherapy agents. However, it is notable that the EXTEND trial was stopped early, leaving the statistical significance of the results in question. Based on this uncertainty, in 2009, the FDA ultimately rejected Cell Therapeutic's initial application for accelerated approval for pixantrone use in relapsed or refractory NHL. Another phase III trial, PIX-R, is now ongoing to clarify pixantrones place in therapy. It will compare pixantrone efficacy to that of gemcitabine. [2]

Structure
Thumb
Synonyms
  • 6,9-bis((2-aminoethyl)amino)benzo(g)isoquinoline-5,10-dione
  • PIX
External IDs
BBR 2778 / BBR-2778
Product Ingredients
IngredientUNIICASInChI Key
Pixantrone dimaleateP0R64C4CR9144675-97-8SVAGFBGXEWPNJC-SPIKMXEPSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PixuvriInjection, powder, for solution29 mgIntravenousCti Life Sciences Limited2012-05-10Not applicableEu
International/Other Brands
Pixuvri (Cell Therapeutics Inc.)
Categories
UNII
F5SXN2KNMR
CAS number
144510-96-3
Weight
Average: 325.372
Monoisotopic: 325.153874872
Chemical Formula
C17H19N5O2
InChI Key
PEZPMAYDXJQYRV-UHFFFAOYSA-N
InChI
InChI=1S/C17H19N5O2/c18-4-7-21-12-1-2-13(22-8-5-19)15-14(12)16(23)10-3-6-20-9-11(10)17(15)24/h1-3,6,9,21-22H,4-5,7-8,18-19H2
IUPAC Name
6,9-bis[(2-aminoethyl)amino]-5H,10H-benzo[g]isoquinoline-5,10-dione
SMILES
NCCNC1=CC=C(NCCN)C2=C1C(=O)C1=C(C=NC=C1)C2=O

Pharmacology

Indication

Currently in Phase III investigation for treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma in patients who have failed two prior lines of therapy. Presently, no standard therapy exists for patients with relapsed or refractory NHL. [2] After first line therapy has been initiated, most patients have received their lifetime limit of doxorubicin and further use of anthracyclines may potentially lead to anthracycline-induced congestive heart failure (CHF). Pixantrone is an attractive alternative as a second line agent, due to its lack of cardiac toxicity. [2]

The phase III trial, PIX-R, is ongoing and will compare pixantrone multidrug therapy with an equivalent regimen in patients with diffuse large B-cell lymphoma (the most common type of NHL).

Previous study results have also suggested the possibility that pixantrone may be safe and effective in doxorubicin naive patients. In myocardial strips which are doxorubicin naive, pixantrone is taken up to a higher degree than in myocardial strips which are doxorubicin exposed, and once absorbed exhibits redox inactivity. [3]

Pixantrone dimaleate has also been investigated as a treatment for acute myelogenous leukemia, diffuse large B-cell lymphoma, follicular lymphoma, metastatic breast cancer, low grade small lymphocytic lymphomas and general metastatic cancers.

Structured Indications
Not Available
Pharmacodynamics

Pixantrone has a wide range of antitumor activity, especially in terms of treating leukemias and lymphomas [3].

Pixantrone lacks cardio-toxic effects. It has postulated that his is because of its redox inactivity and lack and inhibition of doxorubicinol formation in human myocardium. [3]

Mechanism of action

Pixantrone is an aza-anthracenedione which acts as a DNA intercalator. By intercalating between DNA, with modest affinity, it stimulates DNA cleavage by topoisomerase II. (Pixantrone acts as a poison to topoisomerase II by stabilizing protein-DNA complexes which are usually transient, giving rise to double stranded DNA breaks.) However, pixantrone is believed to have additional mechanisms of action as its potency does not correlate to the degree of double stranded DNA breaks observed. It has been postulated that this second mechanism may be pixantrone-DNA adduct formation. [1]

It is important to note that the formation of a pixtantrone-DNA adduct requires pixantrone activation by formaldehyde. Formadehyde may be generated in vitro by hydrogen peroxide, and is derived by various sources in biological systems. It is present in low levels as a result of normal metabolism, and may be present in elevated levels in some haematolgical malignancies. [1] The formation of pixantrone-DNA adducts is thus feasible, and it is believed that a long pixantrone-DNA adduct half life has the potential to maximize DNA damage. It may do so by enhancing the disruption of DNA replication and transcription, and potentially by encourage apoptosis. [1]

In explanation of pixantrones lack of cardiotoxicity, it has been elucidated that pixantrone is structurally similar to mitoxantrone; however, instead of a 5,8-dihydroxyphenyl ring (thought to be responsible for cardiotoxicity) it has a nitrogen heteroatom. This nitrogen heteroatom helps to create additional hydrogen bonding sites amd increases pixantrone interaction with DNA and topoisomerase II. [2]

Pixantrone's lack of a hydroquinone is believed to render it resistant to one electron reduction. In contrast, doxorubicin - which contains a hydroquinone - experiences one electron redox cycling and ROS formation via NADH dehydrogenase. [3] Pixantrone also does not bind iron, and thus does not produce ROS by redox cycling between oxidative states of iron, as other anthracyclines do. [2]

The first line agent doxorubicin is cardiotoxic, in part, due to its ability to redox activate the superoxide anion and hydrogen peroxide, and form a long-lived secondary alcohol metabolite: doxorubicinol. [3] Clearance of doxorubicin from myocardial tissue is incomplete, and it can be found months or years after the last administration. [3] In doxorubicin treated ex vivo cardiac strips, pixantrone formed an N-dealkylated product that inhibited metabolism of residual doxorubicin into doxorubicinol. Additionally, in ex vivo human myocardial strips (doxorubicin naive, and doxorubicin pretreated) pixantrone showed high cardiac uptake without formation of superoxide anion or hydrogen peroxide. Pixantrones lack of cardiotoxicity is thus attributed to its redox inactivity and inhibition of doxorubicinol formation. [3]

Absorption

Intravenous administration results in a rapid distribution followed by a slow elimination. [2] In ex vivo myocardial strips, pixantrone is taken up to a higher degree than mitoxantrone. In myocardial strips which are doxorubicin naive pixantrone displays higher uptake than in DOX-loaded myocardial strips. DOX clearance causes membrane effects which may be responsible for this observation. DOX clearance involves rapid passive diffusion through one side of the membrane followed by "flip flop" reorientation of the lipid bilayer. This disorganization of lipids is believed to impair membrane penetration by pixantrone. [3]

Volume of distribution

9.7-29.7 L/kg. [2]

Protein binding

Anthracyclines, which may be effective second line treatments for NHL have limited use in therapy because of cumulative cardiotoxicity which may result in irreversible damage to cardiac tissue. [2]

Metabolism

Pixantrone does not form secondary alcohol metabolites. [2] Pixantrone hydrolyzes extensively to CT-45886 which is believed to inhibit doxol formation by displacing DOX from the active site of reductases. CT4889 and CT-45890 are also formed.[3]

Route of elimination

Fecally and renally excreted. Urinary elimination of unchanged drug is less than 10%. [2]

Half life

Half life is 12 hours. [2]

Clearance

Plasma clearance is 0.75 - 1.31 L/h/kg. [2]

Toxicity

Pixantrone appears well tolerated. The most common toxicity is neutropenia. Other toxicities include lymphopenia, thrombocytopenia, alopecia, nausea and vomiting. As pixantrone is a blue compound patients may experience a blue discoloration of the skin and urine. [2]

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

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

References

General References
  1. Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM: Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent. Nucleic Acids Res. 2007;35(11):3581-9. Epub 2007 May 5. [PubMed:17483512]
  2. Jamal-Hanjani M, Pettengell R: Pharmacokinetic evaluation of pixantrone for the treatment of non-Hodgkin's lymphoma. Expert Opin Drug Metab Toxicol. 2011 Nov;7(11):1441-8. doi: 10.1517/17425255.2011.618834. Epub 2011 Sep 12. [PubMed:21905966]
  3. Salvatorelli E, Menna P, Paz OG, Chello M, Covino E, Singer JW, Minotti G: The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients. J Pharmacol Exp Ther. 2013 Feb;344(2):467-78. doi: 10.1124/jpet.112.200568. Epub 2012 Nov 28. [PubMed:23192654]
External Links
PubChem Compound
134019
PubChem Substance
347827761
ChemSpider
118174
ChEBI
135945
ChEMBL
CHEMBL167731
Drugs.com
Drugs.com Drug Page
Wikipedia
Pixantrone
ATC Codes
L01DB11 — Pixantrone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentMetastatic Cancers1
1CompletedTreatmentLymphoma, Low-Grade / Lymphoma, Mixed-Cell, Follicular / Lymphoma, Small Cleaved-Cell, Follicular / Small Lymphocytic Lymphoma (SLL)1
1RecruitingNot AvailableMalignant Lymphomas / Solid Tumor (Excluding CNS)1
1Unknown StatusTreatmentMalignant Lymphomas1
1, 2Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
1, 2CompletedTreatmentAcute Myelogenous Leukaemia (AML)1
2Active Not RecruitingTreatmentCancer, Breast1
2RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
2Unknown StatusTreatmentMalignant Lymphomas1
3Active Not RecruitingTreatmentDe Novo DLBCL / DLBCL Transformed From Indolent Lymphoma / Follicular Grade 3 Lymphoma / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
3CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
3TerminatedTreatmentFollicular Lymphoma (FL) / Lymphoma, Low-Grade / Lymphoma, Mixed-Cell, Follicular / Lymphoma, Small Cleaved-Cell, Follicular1
3TerminatedTreatmentNon-Hodgkin's Lymphoma (NHL)1
3Unknown StatusTreatmentLeukemias / Malignant Lymphomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous29 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.494 mg/mLALOGPS
logP0.57ALOGPS
logP0.35ChemAxon
logS-2.8ALOGPS
pKa (Strongest Basic)9.52ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area123.13 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity95.28 m3·mol-1ChemAxon
Polarizability35.09 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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 isoquinoline quinones. These are isoquinoline derivative with a structure containing a 5,8-dihydroisoquinoline-5,8-dione skeleton.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoquinolines and derivatives
Sub Class
Isoquinoline quinones
Direct Parent
Isoquinoline quinones
Alternative Parents
Naphthalenes / Pyridinecarboxylic acids and derivatives / Aryl ketones / Secondary alkylarylamines / Vinylogous amides / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Monoalkylamines
show 1 more
Substituents
Isoquinoline quinone / Naphthalene / Pyridine carboxylic acid or derivatives / Aryl ketone / Secondary aliphatic/aromatic amine / Benzenoid / Pyridine / Heteroaromatic compound / Vinylogous amide / Ketone
show 13 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Drug created on March 19, 2008 10:16 / Updated on November 09, 2017 03:53