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:

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

Clostridium 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

Target	Actions	Organism
AClostridium difficile Toxin B	antibody neutralizer	Peptoclostridium difficile

Absorption

After a single intravenous dose of 10 mg/kg bezlotoxumab, geometric mean AUC_0-∞ and C_max 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.

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Bezlotoxumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Bezlotoxumab.
Aducanumab	The risk or severity of adverse effects can be increased when Aducanumab is combined with Bezlotoxumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Bezlotoxumab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Bezlotoxumab.
Amivantamab	The risk or severity of adverse effects can be increased when Bezlotoxumab is combined with Amivantamab.
Anifrolumab	The risk or severity of adverse effects can be increased when Anifrolumab is combined with Bezlotoxumab.
Ansuvimab	The risk or severity of adverse effects can be increased when Bezlotoxumab is combined with Ansuvimab.
Anthrax immune globulin human	The risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Bezlotoxumab.
Antilymphocyte immunoglobulin (horse)	The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Bezlotoxumab.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Zinplava	Injection, solution, concentrate	25 mg/ml	Intravenous	Merck Sharp & Dohme B.V.	2020-12-18	Not applicable
Zinplava	Injection, solution	25 mg/1mL	Intravenous	Merck Sharp & Dohme Llc	2016-10-21	Not applicable
Zinplava	Injection, solution, concentrate	25 mg/ml	Intravenous	Merck Sharp & Dohme B.V.	2023-07-22	Not applicable

Chemical Identifiers

UNII: 4H5YMK1H2E
CAS number: 1246264-45-8

References

General References

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]
Markham A: Bezlotoxumab: First Global Approval. Drugs. 2016 Dec;76(18):1793-1798. doi: 10.1007/s40265-016-0673-1. [Article]
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]
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]
FDA Approved Drug Products: ZINPLAVA (bezlotoxumab) injection, for intravenous use (October 2016) [Link]
FDA Approved Drug Products: ZINPLAVA (bezlotoxumab) injection, for intravenous use (May 2023) [Link]
Merck: Bezlotoxumab MSDS [Link]
EMA Approved Drug Products: ZINPLAVA (bezlotoxumab) Intravenous Infusion [Link]

External Links

PubChem Substance: 347911429
RxNav: 1855048
Wikipedia: Bezlotoxumab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Clostridium difficile infection recurrence	1
4	Recruiting	Prevention	C. Diff. Infections / Crohn's Disease (CD) / Inflammatory Bowel Diseases (IBD) / Ulcerative Colitis	1
4	Terminated	Prevention	Clostridium Difficile	1
4	Terminated	Treatment	Clostridium Difficle Colitis / Clostridium; Sepsis	1
4	Unknown Status	Prevention	Clostridium difficile infection recurrence	1
4	Withdrawn	Treatment	Clostridioides Difficile / Clostridium Infections / Pseudomembranous Enterocolitis	1
3	Completed	Prevention	Clostridium Difficile Infection (CDI)	1
3	Completed	Treatment	Clostridium Difficile Infection (CDI)	2
2	Active Not Recruiting	Treatment	Clostridioides Difficile Infection / Clostridium difficile infection recurrence / Death / Organ Dysfunction Syndrome / Stool Microbiome	1
2	Completed	Treatment	Clostridium Infections	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous	25 mg/1mL
Injection, solution, concentrate	Intravenous	25 mg/ml
Injection, solution, concentrate	Intravenous; Parenteral	25 MG/ML

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Clostridium difficile Toxin B

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

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

Bezlotoxumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References