Pixantrone

Identification

Summary

Pixantrone is an antineoplastic agent use to treat patients with relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL).

Brand Names

Pixuvri

Generic Name

Pixantrone

DrugBank Accession Number

DB06193

Background

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]

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 325.372
Monoisotopic: 325.153874872
Chemical Formula: C₁₇H₁₉N₅O₂

Synonyms

6,9-bis((2-aminoethyl)amino)benzo(g)isoquinoline-5,10-dione
Pixantrona
Pixantrone

External IDs

BBR 2778
BBR-2778

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Non-hodgkin's lymphoma, relapsed		••••••••••••	•••••		•••••••••
Treatment of	Refractory non-hodgkin's lymphoma		••••••••••••	•••••		•••••••••

Contraindications & Blackbox Warnings

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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]

Adverse Effects

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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]

Pathways

Not Available

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Not Available

Interactions

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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
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Ambroxol	The risk or severity of methemoglobinemia can be increased when Pixantrone is combined with Ambroxol.
Articaine	The risk or severity of methemoglobinemia can be increased when Pixantrone is combined with Articaine.
Benzocaine	The risk or severity of methemoglobinemia can be increased when Pixantrone is combined with Benzocaine.
Benzyl alcohol	The risk or severity of methemoglobinemia can be increased when Pixantrone is combined with Benzyl alcohol.
Bupivacaine	The risk or severity of methemoglobinemia can be increased when Pixantrone is combined with Bupivacaine.

Food Interactions

No interactions found.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Pixantrone dimaleate	P0R64C4CR9	144675-97-8	SVAGFBGXEWPNJC-SPIKMXEPSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Pixuvri	Injection, powder, for solution	29 mg	Intravenous	Les Laboratoires Servier	2016-09-08	Not applicable

Chemical Identifiers

UNII: F5SXN2KNMR
CAS number: 144510-96-3
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

References

General References

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. [Article]
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. [Article]
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. [Article]

External Links

PubChem Compound: 134019
PubChem Substance: 347827761
ChemSpider: 118174
ChEBI: 135945
ChEMBL: CHEMBL167731
ZINC: ZINC000001535903
Drugs.com: Drugs.com Drug Page
Wikipedia: Pixantrone

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	Completed	Treatment	De Novo DLBCL / Diffuse Large B-Cell Lymphoma (DLBCL) / DLBCL Transformed From Indolent Lymphoma / Grade 3 Follicular Lymphoma	1
3	Completed	Treatment	Non-Hodgkin's Lymphoma (NHL)	1
3	Terminated	Treatment	Follicular Lymphoma ( FL) / Follicular Small Cleaved Cell Lymphoma / Low Grade Lymphoma / Lymphoma, Mixed-Cell, Follicular	1
3	Withdrawn	Treatment	Leukemias / Lymphoma	1
3	Withdrawn	Treatment	Non-Hodgkin's Lymphoma (NHL) / Non-Hodgkin's Lymphomas	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	29 mg
Injection, powder, for solution	Intravenous; Parenteral	29 MG

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.494 mg/mL	ALOGPS
logP	0.57	ALOGPS
logP	0.35	Chemaxon
logS	-2.8	ALOGPS
pKa (Strongest Basic)	9.52	Chemaxon
Physiological Charge	2	Chemaxon
Hydrogen Acceptor Count	7	Chemaxon
Hydrogen Donor Count	4	Chemaxon
Polar Surface Area	123.13 Å²	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	95.28 m³·mol^-1	Chemaxon
Polarizability	35.09 Å³	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a6r-0009000000-923b267183c0d4a2d31a
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-0009000000-b01458aca84b7af92845
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a6r-0019000000-a9d74a6935531b14fe50
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-0049000000-2f976d9729e00434172c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0ged-0092000000-42d2b5e228a60b456871
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udr-0090000000-5b222e3b8d0ed910a565
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	193.5147033	predicted	DarkChem Lite v0.1.0
[M-H]-	173.45572	predicted	DeepCCS 1.0 (2019)
[M+H]+	193.7744033	predicted	DarkChem Lite v0.1.0
[M+H]+	175.81372	predicted	DeepCCS 1.0 (2019)
[M+Na]+	193.8466033	predicted	DarkChem Lite v0.1.0
[M+Na]+	182.33058	predicted	DeepCCS 1.0 (2019)

Drug created at March 19, 2008 16:16 / Updated at January 02, 2024 23:49

Pixantrone

Identification

Structure for Pixantrone (DB06193)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)