Bendamustine

Identification

Name
Bendamustine
Accession Number
DB06769
Description

Bendamustine is a nitrogen mustard drug indicated for use in the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action is unknown.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 358.263
Monoisotopic: 357.101082345
Chemical Formula
C16H21Cl2N3O2
Synonyms
  • Bendamustina
  • Bendamustine
  • Ribomustine
External IDs
  • SDX 105
  • SDX-105
  • SDX105

Pharmacology

Indication

Bendamustine is indicated for use in the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

No mean changes in QTc interval greater than 20 milliseconds were detected up to one hour post-infusion.

Mechanism of action

Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action is unknown.

Absorption

Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.

Volume of distribution

The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20-25 L. Steady-state volume of distribution for total radioactivity was approximately 50 L, indicating that neither bendamustine nor total radioactivity are extensively distributed into the tissues.

Protein binding

In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs.

Metabolism

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10th and 1/100th that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine. Results of a human mass balance study confirm that bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways.

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Route of elimination

Mean recovery of total radioactivity in cancer patients following IV infusion of [14C] bendamustine hydrochloride was approximately 76% of the dose. Approximately 50% of the dose was recovered in the urine and approximately 25% of the dose was recovered in the feces. Urinary excretion was confirmed as a relatively minor pathway of elimination of bendamustine, with approximately 3.3% of the dose recovered in the urine as parent. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.

Half-life

40 minutes

Clearance

700 mL/min

Adverse Effects
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Toxicity

Risk for tumor-lysis syndrome. Discontinue use in the event of severe/progressive skin reactions. Hematologic malignancies of different forms reported. Discontinue use in the case of severe infusion reactions. May cause extravasation. Mild to moderate renal impairment. Mild hepatic impairment. Sepsis (infections) may occur. Avoid use if pregnant. Possibility of anaphylaxis or infusion reactions- severe in rare cases.

Affected organisms
Not Available
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 Bendamustine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Bendamustine can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Bendamustine.
AbirateroneThe serum concentration of Bendamustine can be increased when it is combined with Abiraterone.
AcenocoumarolThe metabolism of Bendamustine can be decreased when combined with Acenocoumarol.
AcetaminophenThe metabolism of Bendamustine can be decreased when combined with Acetaminophen.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Bendamustine.
AcyclovirThe metabolism of Bendamustine can be decreased when combined with Acyclovir.
AdalimumabThe metabolism of Bendamustine can be increased when combined with Adalimumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Bendamustine.
Additional Data Available
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  • Severity
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  • Evidence Level
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  • Action
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Bendamustine hydrochloride981Y8SX18M3543-75-7ZHSKUOZOLHMKEA-UHFFFAOYSA-N
Bendamustine hydrochloride monohydrateNot Available1374784-02-7TWBJYCLUHINEDN-UHFFFAOYSA-N
International/Other Brands
Levact (NAPP Pharmaceuticals ) / Treakisym (Teva Pharmaceutical Industries Ltd.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BelrapzoInjection100 mg/1IntravenousEagle Pharmaceuticals, Inc2019-06-03Not applicableUS flag
Bendamustine HydrochlorideInjection100 mg/1IntravenousEagle Pharmaceuticals, Inc2018-05-152020-09-30US flag
BendekaInjection, solution25 mg/1mLIntravenousTeva Pharmaceuticals USA, Inc.2015-12-08Not applicableUS flag
TreandaInjection, solution, concentrate180 mg/2mLIntravenousCephalon, Inc.2014-11-052017-05-31US flag
TreandaInjection, powder, lyophilized, for solution100 mg/20mLIntravenousCephalon, Inc.2008-03-31Not applicableUS flag
TreandaInjection, solution, concentrate45 mg/0.5mLIntravenousCephalon, Inc.2014-11-052017-04-30US flag
TreandaPowder, for solution100 mgIntravenousTEVA Canada Limited2012-09-12Not applicableCanada flag
TreandaInjection, powder, lyophilized, for solution25 mg/5mLIntravenousCephalon, Inc.2010-01-05Not applicableUS flag
TreandaPowder, for solution25 mgIntravenousTEVA Canada Limited2012-09-12Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number
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    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Bendamustine HydrochlorideInjection, powder, lyophilized, for solution100 mg/20mLIntravenousMylan Institutional LLC2018-04-26Not applicableUS flag
Bendamustine HydrochlorideInjection, powder, lyophilized, for solution25 mg/5mLIntravenousMylan Institutional LLC2018-04-26Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
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Categories

ATC Codes
L01AA09 — Bendamustine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzimidazoles
Sub Class
Not Available
Direct Parent
Benzimidazoles
Alternative Parents
Nitrogen mustard compounds / Dialkylarylamines / N-substituted imidazoles / Benzenoids / Heteroaromatic compounds / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds
show 5 more
Substituents
Alkyl chloride / Alkyl halide / Amine / Amino acid / Amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzimidazole
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
9266D9P3PQ
CAS number
16506-27-7
InChI Key
YTKUWDBFDASYHO-UHFFFAOYSA-N
InChI
InChI=1S/C16H21Cl2N3O2/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23/h5-6,11H,2-4,7-10H2,1H3,(H,22,23)
IUPAC Name
4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-1,3-benzodiazol-2-yl}butanoic acid
SMILES
CN1C(CCCC(O)=O)=NC2=CC(=CC=C12)N(CCCl)CCCl

References

General References
  1. Hartmann JT, Mayer F, Schleicher J, Horger M, Huober J, Meisinger I, Pintoffl J, Kafer G, Kanz L, Grunwald V: Bendamustine hydrochloride in patients with refractory soft tissue sarcoma: a noncomparative multicenter phase 2 study of the German sarcoma group (AIO-001). Cancer. 2007 Aug 15;110(4):861-6. [PubMed:17599772]
  2. Bagchi S: Bendamustine for advanced sarcoma. Lancet Oncol. 2007 Aug;8(8):674. [PubMed:17726779]
  3. Dennie TW, Kolesar JM: Bendamustine for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Clin Ther. 2009;31 Pt 2:2290-311. doi: 10.1016/j.clinthera.2009.11.031. [PubMed:20110042]
  4. Teichert J, Baumann F, Chao Q, Franklin C, Bailey B, Hennig L, Caca K, Schoppmeyer K, Patzak U, Preiss R: Characterization of two phase I metabolites of bendamustine in human liver microsomes and in cancer patients treated with bendamustine hydrochloride. Cancer Chemother Pharmacol. 2007 May;59(6):759-70. Epub 2006 Sep 7. [PubMed:16957931]
  5. Darwish M, Bond M, Hellriegel E, Robertson P Jr, Chovan JP: Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol. 2015 Jun;75(6):1143-54. doi: 10.1007/s00280-015-2727-6. Epub 2015 Apr 1. [PubMed:25829094]
KEGG Drug
D07085
PubChem Compound
65628
PubChem Substance
310264882
ChemSpider
59069
BindingDB
173621
RxNav
134547
ChEBI
135515
ChEMBL
CHEMBL487253
ZINC
ZINC000004214955
Wikipedia
Bendamustine
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (170 KB)
MSDS
Download (174 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAdvanced Follicular Lymphoma1
4CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)3
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma1
3Active Not RecruitingTreatmentFollicular Lymphoma (FL)2
3Active Not RecruitingTreatmentFollicular Non-Hodgkin's Lymphoma1
3Active Not RecruitingTreatmentMalignant Lymphomas1
3Active Not RecruitingTreatmentMantle Cell Lymphoma (MCL)1
3Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)2
3Active Not RecruitingTreatmentStage I Chronic Lymphocytic Leukemia / Stage II Chronic Lymphocytic Leukemia / Stage III Chronic Lymphocytic Leukemia / Stage IV Chronic Lymphocytic Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous100 mg
InjectionIntravenous25 mg
Injection, powder, for solutionParenteral2.5 MG/ML
InjectionIntravenous100 mg/1
Injection, powder, lyophilized, for solutionIntravenous100 mg/20mL
Injection, powder, lyophilized, for solutionIntravenous25 mg/5mL
Injection, solutionIntravenous25 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous100 mg
Injection, powder, lyophilized, for solutionIntravenous25 mg
Injection, solution, concentrateIntravenous100 mg
Injection, solution, concentrateIntravenous25 mg
Injection, powder, for solutionIntravenous100 mg
Injection, powder, for solutionIntravenous25 mg
Injection, solution, concentrateIntravenous; Parenteral180 MG/4ML
Injection, solution, concentrateIntravenous180 mg/2mL
Injection, solution, concentrateIntravenous45 mg/0.5mL
Powder, for solutionIntravenous100 mg
Powder, for solutionIntravenous25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8791270Yes2014-07-292026-07-12US flag
US8344006Yes2013-01-012030-03-23US flag
US8445524Yes2013-05-212029-09-26US flag
US8669279Yes2014-03-112029-09-26US flag
US8883836Yes2014-11-112029-09-26US flag
US8436190Yes2013-05-072031-04-26US flag
US8895756Yes2014-11-252026-07-12US flag
US8609863Yes2013-12-172026-07-12US flag
US9034908No2015-05-192033-03-15US flag
US9144568No2015-09-292033-03-15US flag
US9000021No2015-04-072033-03-15US flag
US8609707No2013-12-172031-08-11US flag
US9265831No2016-02-232031-01-28US flag
US9533955No2017-01-032029-03-26US flag
US9597397No2017-03-212033-03-15US flag
US9597399No2017-03-212033-03-15US flag
US9597398No2017-03-212033-03-15US flag
US9579384No2017-02-282033-03-15US flag
US9572797No2017-02-212031-01-28US flag
US9572796No2017-02-212031-01-28US flag
US9572887No2017-02-212033-03-15US flag
US10010533No2018-07-032031-01-28US flag
US10052385No2018-08-212033-03-15US flag
Additional Data Available
  • Filed On
    Filed On
    Available for Purchase

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0618 mg/mLALOGPS
logP3.07ALOGPS
logP1.66ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)4.38ChemAxon
pKa (Strongest Basic)6.65ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area58.36 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity92.92 m3·mol-1ChemAxon
Polarizability38.19 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9947
Blood Brain Barrier+0.773
Caco-2 permeable+0.5348
P-glycoprotein substrateSubstrate0.6887
P-glycoprotein inhibitor INon-inhibitor0.8236
P-glycoprotein inhibitor IINon-inhibitor0.7294
Renal organic cation transporterNon-inhibitor0.5462
CYP450 2C9 substrateNon-substrate0.7141
CYP450 2D6 substrateNon-substrate0.7322
CYP450 3A4 substrateSubstrate0.5545
CYP450 1A2 substrateNon-inhibitor0.8012
CYP450 2C9 inhibitorNon-inhibitor0.9027
CYP450 2D6 inhibitorNon-inhibitor0.878
CYP450 2C19 inhibitorNon-inhibitor0.8587
CYP450 3A4 inhibitorNon-inhibitor0.8756
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8882
Ames testNon AMES toxic0.618
CarcinogenicityNon-carcinogens0.9235
BiodegradationNot ready biodegradable0.9798
Rat acute toxicity3.2636 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7196
hERG inhibition (predictor II)Non-inhibitor0.7584
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Teichert J, Baumann F, Chao Q, Franklin C, Bailey B, Hennig L, Caca K, Schoppmeyer K, Patzak U, Preiss R: Characterization of two phase I metabolites of bendamustine in human liver microsomes and in cancer patients treated with bendamustine hydrochloride. Cancer Chemother Pharmacol. 2007 May;59(6):759-70. Epub 2006 Sep 7. [PubMed:16957931]
  2. Bendamustine FDA label [File]

Drug created on September 14, 2010 10:21 / Updated on December 02, 2020 09:05

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