Bezlotoxumab

Identification

Summary

Bezlotoxumab is a monoclonal antibody used to reduce the recurrence of Clostridium difficile infections.

Brand Names
Zinplava
Generic Name
Bezlotoxumab
DrugBank Accession Number
DB13140
Background

Bezlotoxumab is a fully humanized ImmunoglobulinG1 (IgG1) kappa monoclonal antibody that binds to Clostridium difficile toxin B and neutralizes its effects.6 First approved by the FDA on October 21, 2016,4 bezlotoxumab is used to reduce the recurrence of C. difficile infection.6 On November 22, 2016, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended the granting of a marketing authorization.4 The drug was granted full approval by the EMA on January 18, 2017.8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6464H9974N1726O2014S46
Protein Average Weight
148200.0 Da (approximate)
Sequences
>Bezlotoxumab heavy chain
EVQLVQSGAEVKKSGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIFYPGDSSTRY
SPSFQGQVTISADKSVNTAYLQWSSLKASDTAMYYCARRRNWGNAFDIWGQGTMVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Bezlotoxumab light chain
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSTWTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG DRUG: Bezlotoxumab [Link]
Download FASTA Format
Synonyms
  • Bezlotoxumab
External IDs
  • MBL-CDB1
  • MDX-1388
  • MK-6072

Pharmacology

Indication

Bezlotoxumab is indicated to reduce the recurrence of Clostridioides difficile infection (CDI) in patients who are receiving antibacterial drug treatment for CDI and are at high risk for CDI recurrence.6,8 In the US, the drug is approved for use in patients one year of age and older.6 In Europe, it is approved in adults only.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in prophylaxis ofClostridium difficile infection recurrence•••••••••••••••• •••• •• ••••••••••
Prophylaxis ofClostridium difficile infection recurrence••••••••••••••••••••• •••• •• ••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Bezlotoxumab directly neutralizes the toxic effects of C. difficile by binding to the toxin with high affinity.4,2,6 In vitro, bezlotoxumab inhibited C. difficile toxin B-mediated expression of tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) in human peripheral blood monocyte cells and human colonic and explants.2 In clinical trials, the rate of recurrent C. difficile infection was lower in patients at risk for recurrent C. difficile infection receiving bezlotoxumab compared to placebo.2

The administration of bezlotoxumab plus actoxumab, another antibody directed against the C. difficile toxin resulted in dose-dependent protection against C. difficile toxin-induced damage and inflammation, as well as a reduced recurrence of C. difficile infection in mice.2

Mechanism of action

C. difficile infections are caused by two exotoxins, toxin A and toxin B. Exotoxins are believed to bind to cell surface receptors expressed on colonocytes and are internalized via endocytosis. This process is followed by the acidification of the endosome, leading to a conformation change of the toxin, allowing for the transport of the endosome, autocleavage of the toxin via a cysteine protease domain, and the release of glucosyltransferase domain (GTD) from the endosome to the host cell cytoplasm. GTD glucosylates and inactivates small GTPases, such as Rac and Rho, critical for maintaining the actin cytoskeleton, cell adhesion, epithelial permeability, and other cellular function and homeostasis processes. Exotoxins eventually induce apoptosis and cell loss.1,3 Endotoxins also promote the release of proinflammatory mediators that recruit neutrophils and macrophages to the injury site, further aggravating the gut injury and damage.1 C. difficile infections are associated with a high risk of recurrence.3,4

Bezlotoxumab binds to C. difficile toxin B and neutralizes it.6 According to the findings of surface plasmon resonance analysis, bezlotoxumab binds to the toxin via two epitopes in the C-terminal CROP domain of the toxin, partially blocking the putative receptor binding pockets and preventing it from binding to host cell receptors.2 Bezlotoxumab does not bind to C. difficile toxin A.6

TargetActionsOrganism
AClostridium difficile Toxin B
antibody
neutralizer
Peptoclostridium difficile
Absorption

After a single intravenous dose of 10 mg/kg bezlotoxumab, geometric mean AUC0-∞ and Cmax were 53000 mcg x h/mL and 185 mcg/mL, respectively, in patients with CDI.6

Volume of distribution

Based on a population pharmacokinetic analysis, the geometric mean (%CV) volume of distribution was 7.33 L (16%).5

Protein binding

No information is available.

Metabolism

Bezlotoxumab undergoes protein catabolism.4,5

Route of elimination

Bezlotoxumab is mainly eliminated by catabolism.5

Half-life

Based on a population pharmacokinetic analysis, the geometric mean (%CV) elimination half-life is approximately 19 days (28%).5

Clearance

Based on a population pharmacokinetic analysis, the geometric mean (%CV) clearance of bezlotoxumab was 0.317 L/day (41%). The clearance of bezlotoxumab increased with increasing body weight: the resulting exposure differences are adequately addressed by the administration of a weight-based dose.5

Adverse Effects
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Toxicity

The intravenous LD50 was >125 mg/kg in mice.7 There is no clinical experience with the overdosage of bezlotoxumab.6 In clinical trials, healthy subjects received up to 20 mg/kg, which was generally well tolerated.8 In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be instituted.6

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
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Bezlotoxumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Bezlotoxumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Bezlotoxumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Bezlotoxumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Bezlotoxumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZinplavaInjection, solution, concentrate25 mg/mlIntravenousMerck Sharp & Dohme B.V.2023-07-22Not applicableEU flag
ZinplavaInjection, solution, concentrate25 mg/mlIntravenousMerck Sharp & Dohme B.V.2020-12-18Not applicableEU flag
ZinplavaInjection, solution25 mg/1mLIntravenousMerck Sharp & Dohme Llc2016-10-21Not applicableUS flag

Categories

ATC Codes
J06BC03 — Bezlotoxumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Peptoclostridium difficile

Chemical Identifiers

UNII
4H5YMK1H2E
CAS number
1246264-45-8

References

General References
  1. Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang X, Murgolo N, Ermakov G, DiNunzio E, Racine F, Karczewski J, Secore S, Ingram RN, Mayhood T, Strickland C, Therien AG: Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014 Jun 27;289(26):18008-21. doi: 10.1074/jbc.M114.560748. Epub 2014 May 12. [Article]
  2. Markham A: Bezlotoxumab: First Global Approval. Drugs. 2016 Dec;76(18):1793-1798. doi: 10.1007/s40265-016-0673-1. [Article]
  3. Thandavaram A, Channar A, Purohit A, Shrestha B, Patel D, Shah H, Hanna K, Kaur H, Alazzeh MS, Mohammed L: The Efficacy of Bezlotoxumab in the Prevention of Recurrent Clostridium difficile: A Systematic Review. Cureus. 2022 Aug 13;14(8):e27979. doi: 10.7759/cureus.27979. eCollection 2022 Aug. [Article]
  4. Villafuerte Galvez JA, Kelly CP: Bezlotoxumab: anti-toxin B monoclonal antibody to prevent recurrence of Clostridium difficile infection. Expert Rev Gastroenterol Hepatol. 2017 Jul;11(7):611-622. doi: 10.1080/17474124.2017.1344551. Epub 2017 Jun 26. [Article]
  5. FDA Approved Drug Products: ZINPLAVA (bezlotoxumab) injection, for intravenous use (October 2016) [Link]
  6. FDA Approved Drug Products: ZINPLAVA (bezlotoxumab) injection, for intravenous use (May 2023) [Link]
  7. Merck: Bezlotoxumab MSDS [Link]
  8. EMA Approved Drug Products: ZINPLAVA (bezlotoxumab) Intravenous Infusion [Link]
PubChem Substance
347911429
RxNav
1855048
Wikipedia
Bezlotoxumab

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous25 mg/1mL
Injection, solution, concentrateIntravenous25 mg/ml
Injection, solution, concentrateIntravenous; Parenteral25 MG/ML
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Peptoclostridium difficile
Pharmacological action
Yes
Actions
Antibody
Neutralizer
Curator comments
Bezlotoxumab binds to C. difficile toxin B with an equilibrium dissociation constant (Kd) of <1×10^-9M.
General Function
Glucosyltransferase activity
Specific Function
Cytotoxin.
Gene Name
toxB
Uniprot ID
P18177
Uniprot Name
Toxin B
Molecular Weight
269709.285 Da
References
  1. FDA Approved Drug Products: ZINPLAVA (bezlotoxumab) injection, for intravenous use (May 2023) [Link]

Drug created at November 02, 2016 18:42 / Updated at July 05, 2023 20:26