Identification

Summary

Bendamustineis an antineoplastic agent used for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed following rituximab therapy.

Brand Names
Belrapzo, Bendeka, Treanda
Generic Name
Bendamustine
DrugBank Accession Number
DB06769
Background

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
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.

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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.

Pathways
Not Available
Pharmacogenomic Effects/ADRsBrowse all" title="" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug InteractionsLearn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
Abametapir The serum concentration of Bendamustine can be increased when it is combined with Abametapir.
Abatacept The metabolism of Bendamustine can be increased when combined with Abatacept.
Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Bendamustine.
Abiraterone The serum concentration of Bendamustine can be increased when it is combined with Abiraterone.
Abrocitinib The serum concentration of Bendamustine can be increased when it is combined with Abrocitinib.
Acenocoumarol The metabolism of Bendamustine can be decreased when combined with Acenocoumarol.
Acetaminophen The metabolism of Bendamustine can be decreased when combined with Acetaminophen.
Acetylsalicylic acid The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Bendamustine.
Acyclovir The metabolism of Bendamustine can be decreased when combined with Acyclovir.
Adalimumab The metabolism of Bendamustine can be increased when combined with Adalimumab.
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Food Interactions
No interactions found.

Products

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Product Ingredients
Ingredient UNII CAS InChI Key
Bendamustine hydrochloride 981Y8SX18M 3543-75-7 ZHSKUOZOLHMKEA-UHFFFAOYSA-N
Bendamustine hydrochloride monohydrate X15906D285 1374784-02-7 TWBJYCLUHINEDN-UHFFFAOYSA-N
International/Other Brands
Levact (NAPP Pharmaceuticals )/Treakisym (Teva Pharmaceutical Industries Ltd.)
Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image
Belrapzo Injection 100 mg/1 Intravenous Eagle Pharmaceuticals, Inc 2019-06-03 Not applicable US flag
Bendamustine Hydrochloride Injection 100 mg/1 Intravenous Eagle Pharmaceuticals, Inc 2018-05-15 2020-09-30 US flag
Bendamustine Hydrochloride for Injection Powder, for solution 100 mg / vial Intravenous Mylan Pharmaceuticals 2021-03-12 Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 25 mg / vial Intravenous Accord Healthcare Inc 2021-03-02 Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 100 mg / vial Intravenous Jamp Pharma Corporation 2021-05-06 Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 25 mg / vial Intravenous Mylan Pharmaceuticals 2021-05-28 Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 100 mg / vial Intravenous Hikma Canada Limited Not applicable Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 100 mg / vial Intravenous Auro Pharma Inc 2021-03-02 Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 25 mg / vial Intravenous Jamp Pharma Corporation 2021-05-06 Not applicable Canada flag
Bendamustine Hydrochloride for Injection Powder, for solution 100 mg / vial Intravenous Accord Healthcare Inc 2021-03-02 Not applicable Canada flag
Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image
Bendamustine Hydrochloride Injection, powder, lyophilized, for solution 100 mg/20mL Intravenous Mylan Institutional LLC 2018-04-26 Not applicable US flag
Bendamustine Hydrochloride Injection, powder, lyophilized, for solution 25 mg/5mL Intravenous Mylan Institutional LLC 2018-04-26 Not applicable US flag
Nat-bendamustine Powder, for solution 100 mg / vial Intravenous Natco Pharma Limited 2021-02-25 Not applicable Canada flag
Nat-bendamustine Powder, for solution 25 mg / vial Intravenous Natco Pharma Limited 2021-02-25 Not applicable Canada flag

Categories

ATC Codes
L01AA09 — Bendamustine
Drug Categories
Chemical TaxonomyProvided byClassyfire
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/苯环型的s/Heteroaromatic compounds/Amino acids/Monocarboxylic acids and derivatives/Carboxylic acids/Azacyclic化合物/Organopnictogen compounds
show 5 more
Substituents
Alkyl chloride/Alkyl halide/Amine/Amino acid/Amino acid or derivatives/芳香heteropolycyclic排版ound/Azacycle/Azole/苯环型的/Benzimidazole
show 20 more
Molecular Framework
芳香heteropolycyclic排版ounds
External Descriptors
Not Available
Affected organisms
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(预备(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. [Article]
  2. Bagchi S: Bendamustine for advanced sarcoma. Lancet Oncol. 2007 Aug;8(8):674. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
KEGG Drug
D07085
PubChem Compound
65628
PubChem Substance
310264882
ChemSpider
59069
BindingDB
173621
RxNav
134547
ChEBI
135515
ChEMBL
CHEMBL487253
ZINC
ZINC000004214955
Wikipedia
Bendamustine
FDA label
Download (170 KB)
MSDS
Download (174 KB)

Clinical Trials

Clinical TrialsLearn More" title="" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count
4 Active Not Recruiting Treatment Advanced Follicular Lymphoma 1
4 Completed Treatment Chronic Lymphocytic Leukemia (CLL) 1
3 Active Not Recruiting Treatment Chronic Lymphocytic Leukemia (CLL) 2
3 Active Not Recruiting Treatment Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma 2
3 Active Not Recruiting Treatment Follicular Lymphoma ( FL) 2
3 Active Not Recruiting Treatment Malignant Lymphomas 1
3 Active Not Recruiting Treatment Mantle Cell Lymphoma (MCL) 1
3 Active Not Recruiting Treatment Non-Hodgkin's Lymphoma (NHL) 1
3 Active Not Recruiting Treatment Refractory Angioimmunoblastic T-cell Lymphoma/Relapsed Angioimmunoblastic T-Cell Lymphoma 1
3 Active Not Recruiting Treatment Stage I Chronic Lymphocytic Leukemia/Stage II Chronic Lymphocytic Leukemia/Stage III Chronic Lymphocytic Leukemia/Stage IV Chronic Lymphocytic Leukemia 1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Form Route Strength
Injection Intravenous
Injection, powder, lyophilized, for solution Intravenous 100.00 mg
Injection, powder, lyophilized, for solution Intravenous 25.00 mg
Injection, powder, for solution Parenteral 2.5 mg/ml
Injection, powder, for solution Parenteral
Injection Intravenous 100 mg/1
Injection, powder, lyophilized, for solution Intravenous 100 mg/20mL
Injection, powder, lyophilized, for solution Intravenous 25 mg/5mL
Powder 100 mg
Powder 25 mg
Injection, solution Intravenous 25 mg/1mL
Solution Intravenous 25 mg / mL
Injection, powder, lyophilized, for solution Intravenous
Solution Intravenous 45 mg / mL
Injection Parenteral
Injection, powder, for solution
Solution, concentrate Intravenous 45 mg
Injection, powder, for solution; powder
Powder
Powder 100 mg/1vial
Injection, powder, for solution Intravenous
Powder 25 mg/1vial
Injection, solution, concentrate Intravenous; Parenteral 180 MG/4ML
Injection, powder, lyophilized, for solution Intravenous 100 mg
Injection, powder, lyophilized, for solution Intravenous 25 mg
Injection, solution, concentrate Intravenous 180 mg/2mL
Injection, solution, concentrate Intravenous 45 mg/0.5mL
Powder, for solution Intravenous 100 mg / vial
Powder, for solution Intravenous 25 mg / vial
Prices
Not Available
Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region
US8791270 Yes 2014-07-29 2026-07-12 US flag
US8344006 Yes 2013-01-01 2030-03-23 US flag
US8445524 Yes 2013-05-21 2029-09-26 US flag
US8669279 Yes 2014-03-11 2029-09-26 US flag
US8883836 Yes 2014-11-11 2029-09-26 US flag
US8436190 Yes 2013-05-07 2031-04-26 US flag
US8895756 Yes 2014-11-25 2026-07-12 US flag
US8609863 Yes 2013-12-17 2026-07-12 US flag
US9034908 No 2015-05-19 2033-03-15 US flag
US9144568 No 2015-09-29 2033-03-15 US flag
US9000021 No 2015-04-07 2033-03-15 US flag
US8609707 No 2013-12-17 2031-08-11 US flag
US9265831 No 2016-02-23 2031-01-28 US flag
US9533955 No 2017-01-03 2029-03-26 US flag
US9597397 No 2017-03-21 2033-03-15 US flag
US9597399 No 2017-03-21 2033-03-15 US flag
US9597398 No 2017-03-21 2033-03-15 US flag
US9579384 No 2017-02-28 2033-03-15 US flag
US9572797 No 2017-02-21 2031-01-28 US flag
US9572796 No 2017-02-21 2031-01-28 US flag
US9572887 No 2017-02-21 2033-03-15 US flag
US10010533 No 2018-07-03 2031-01-28 US flag
US10052385 No 2018-08-21 2033-03-15 US flag
US11103483 No 2021-08-31 2031-01-28 US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
Property Value Source
Water Solubility 0.0618 mg/mL ALOGPS
logP 3.07 ALOGPS
logP 1.8 ChemAxon
logS -3.8 ALOGPS
pKa (Strongest Acidic) 4.36 ChemAxon
pKa (Strongest Basic) 6.41 ChemAxon
Physiological Charge -1 ChemAxon
Hydrogen Acceptor Count 4 ChemAxon
Hydrogen Donor Count 1 ChemAxon
Polar Surface Area 58.36 Å2 ChemAxon
Rotatable Bond Count 9 ChemAxon
Refractivity 92.92 m3·mol-1 ChemAxon
Polarizability 38.19 Å3 ChemAxon
Number of Rings 2 ChemAxon
生物利用度 1 ChemAxon
Rule of Five Yes ChemAxon
Ghose Filter Yes ChemAxon
Veber's Rule No ChemAxon
MDDR-like Rule No ChemAxon
Predicted ADMET Features
Property Value Probability
Human Intestinal Absorption + 0.9947
Blood Brain Barrier + 0.773
Caco-2 permeable + 0.5348
P-glycoprotein substrate Substrate 0.6887
P-glycoprotein inhibitor I Non-inhibitor 0.8236
P-glycoprotein inhibitor II Non-inhibitor 0.7294
Renal organic cation transporter Non-inhibitor 0.5462
CYP450 2C9 substrate Non-substrate 0.7141
CYP450 2D6 substrate Non-substrate 0.7322
CYP450 3A4 substrate Substrate 0.5545
CYP450 1A2 substrate Non-inhibitor 0.8012
CYP450 2C9 inhibitor Non-inhibitor 0.9027
CYP450 2D6 inhibitor Non-inhibitor 0.878
CYP450 2C19 inhibitor Non-inhibitor 0.8587
CYP450 3A4 inhibitor Non-inhibitor 0.8756
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8882
Ames test Non AMES toxic 0.618
Carcinogenicity Non-carcinogens 0.9235
Biodegradation Not ready biodegradable 0.9798
Rat acute toxicity 3.2636 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7196
hERG inhibition (predictor II) Non-inhibitor 0.7584
ADMET data is predicted usingadmetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Spectrum Spectrum Type Splash Key
预测MS / MS谱- 10V, Positive (Annotated) Predicted LC-MS/MS Not Available
预测MS / MS谱- 20V, Positive (Annotated) Predicted LC-MS/MS Not Available
预测MS / MS谱- 40V, Positive (Annotated) Predicted LC-MS/MS Not Available
预测MS / MS谱- 10V, Negative (Annotated) Predicted LC-MS/MS Not Available
预测MS / MS谱- 20V, Negative (Annotated) Predicted LC-MS/MS Not Available
预测MS / MS谱- 40V, Negative (Annotated) Predicted LC-MS/MS Not 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
分子量
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. [Article]
  2. Bendamustine FDA label [File]

Drug created at September 14, 2010 16:21 / Updated at October 16, 2022 02:33