Siltuximab

Identification

Summary

Siltuximab is an interleukin antagonist used to treat multicentric Castleman's disease (MCD) in patients who are HIV and HHV-8 negative.

Brand Names

Sylvant

Generic Name

Siltuximab

DrugBank Accession Number

DB09036

Background

Siltuximab is a chimeric (human-mouse) monoclonal immunoglobulin G1-kappa antibody produced in a Chinese hamster ovary (CHO) cell line by recombinant DNA technology. Siltuximab prevents the binding of IL-6 to soluble and membrane-bound IL-6 receptors by forming high affinity complexes with human interleukin-6 (IL-6). Its use is indicated for the treatment of adult patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. MCD is a rare blood disorder caused by dysregulated IL-6 production, proliferation of lymphocytes, and subsequent enlargement of the lymph nodes. It is administered as a 1 hour intravenous infusion every 3 weeks.

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula

C₆₄₅₀H₉₉₃₂N₁₆₈₈O₂₀₁₆S₅₀

Protein Average Weight

145000.0 Da

Sequences

>Heavy Chain Sequence
EVQLVESGGKLLKPGGSLKLSCAASGFTFSSFAMSWFRQSPEKRLEWVAEISSGGSYTYY
PDTVTGRFTISRDNAKNTLYLEMSSLRSEDTAMYYCARGLWGYYALDYWGQGTSVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK

>Light Chain Sequence
QIVLIQSPAIMSASPGEKVTMTCSASSSVSYMYWYQQKPGSSPRLLIYDTSNLASGVPVR
FSGSGSGTSYSLTISRMEAEDAATYYCQQWSGYPYTFGGGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Download FASTA Format

Synonyms

• Siltuximab

External IDs

• CLLB8
• CNTO 328
• CNTO-328
• CNTO328

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Pharmacology

Indication

Siltuximab is indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Siltuximab did not bind to virally produced IL-6 in a nonclinical study and was therefore not studied in patients with MCD who are HIV or HHV-8 positive.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Castleman's disease		••••••••••••		••••• ••••••••••••• ••••••••• ••• ••••••••	•••••••••

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Pharmacodynamics

Siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods, therefore measurement of serum or plasma IL-6 concentrations should not be used as a pharmacodynamic marker during treatment. As well, cytochrome P450 enzymes in the liver are down regulated by infection and inflammation stimuli, which includes cytokines such as IL-6. By preventing IL-6 signalling through treatment with siltuximab, CYP450 activity may be increased leading to faster metabolism of drugs that are CYP450 substrates.

Mechanism of action

Siltuximab complexes with human IL-6 and prevents binding to soluble and membrane-bound IL-6 receptors, thereby inhibiting the proliferation of lymphocytes.

Target	Actions	Organism
AInterleukin-6	antagonist antibody	Humans

Absorption

Not Available

Volume of distribution

Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L.

Protein binding

Not Available

Metabolism

As siltuximab is an antibody, the expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance.

Route of elimination

Not Available

Half-life

The mean terminal half life after the first intravenous infusion of 11 mg/kg is 20.6 days.

Clearance

Body weight was identified as the only statistically significant covariate of siltuximab clearance, therefore body weight based dosing is appropriate. Based on population pharmacokinetic analysis, the clearance of situximab in patients is 0.23 L/day.

Adverse Effects

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Toxicity

The most common side effects that occurred during siltuximab treatment were pruritis, increased weight, rash, hyperuricemia, and upper respiratory tract infection. Siltuximab should not be administered to patients with severe infections as it may mask signs and symptoms of acute inflammation including suppression of fever and acute phase reactants such as C-reactive protein (CRP). Gastrointestinal perforation has been reported in clinical trials, therefore use with caution in patients who may be at increased risk for GI perforation.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" 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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Siltuximab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Siltuximab.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Siltuximab.
Abrocitinib	The metabolism of Abrocitinib can be increased when combined with Siltuximab.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Siltuximab.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Sylvant	Injection, powder, for solution	100 mg	Intravenous	Recordati Netherlands B.V.	2020-12-23	Not applicable
Sylvant	Injection, powder, for solution	400 mg/1	Intravenous	EUSA Pharma (UK) Ltd	2014-04-23	Not applicable
Sylvant	Injection, powder, lyophilized, for solution	400 mg/1	Intravenous	Janssen Biotech, Inc.	2014-04-01	2021-01-31
Sylvant	Powder, for solution	100 mg / vial	Intravenous	Eusa Pharma (Uk) Limited	2015-03-03	Not applicable
Sylvant	Injection, powder, for solution	400 mg	Intravenous	Recordati Netherlands B.V.	2020-12-23	Not applicable

Categories

ATC Codes

L04AC11 — Siltuximab

• L04AC — Interleukin inhibitors
• L04A — IMMUNOSUPPRESSANTS
• L04 — IMMUNOSUPPRESSANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Agents reducing cytokine levels
• Amino Acids, Peptides, and Proteins
• Antibodies
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Blood Proteins
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (weak)
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Globulins
• Immunoglobulins
• Immunoproteins
• Immunosuppressive Agents
• Immunotherapy
• Interleukin Inhibitors
• Interleukin-6 Antagonist
• Proteins
• Serum Globulins

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

Not Available

Chemical Identifiers

UNII

T4H8FMA7IM

CAS number

541502-14-1

References

General References

1. Puchalski T, Prabhakar U, Jiao Q, Berns B, Davis HM: Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2010 Mar 1;16(5):1652-61. doi: 10.1158/1078-0432.CCR-09-2581. Epub 2010 Feb 23. [Article]
2. Deisseroth A, Ko CW, Nie L, Zirkelbach JF, Zhao L, Bullock J, Mehrotra N, Del Valle P, Saber H, Sheth C, Gehrke B, Justice R, Farrell A, Pazdur R: FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease. Clin Cancer Res. 2015 Mar 1;21(5):950-4. doi: 10.1158/1078-0432.CCR-14-1678. Epub 2015 Jan 19. [Article]
3. Liu YC, Stone K, van Rhee F: Siltuximab for multicentric Castleman disease. Expert Rev Hematol. 2014 Oct;7(5):545-57. doi: 10.1586/17474086.2014.946402. Epub 2014 Aug 9. [Article]

External Links

KEGG Drug

D09669

PubChem Substance

347910394

RxNav

1535218

ChEMBL

CHEMBL1743070

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Siltuximab

FDA label

Download (326 KB)

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	Coronavirus Disease 2019 (COVID‑19)	1
3	Terminated	Treatment	Acute Respiratory Distress Syndrome (ARDS) / Coronavirus Disease 2019 (COVID‑19) / Lung Disorder / Pneumonia / Respiratory Tract Diseases / Respiratory Tract Infections (RTI)	1
3	Withdrawn	Treatment	Multiple Myeloma (MM)	1
2	Active Not Recruiting	Treatment	Multiple Myeloma (MM) / Primary Amyloidosis	1
2	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	100 mg/1
Injection, powder, for solution	Intravenous	400 mg/1
Injection, powder, for solution	Intravenous; Parenteral	100 MG
Injection, powder, for solution	Intravenous; Parenteral	400 MG
Injection, powder, lyophilized, for solution	Intravenous	100 mg/1
Injection, powder, lyophilized, for solution	Intravenous	400 mg/1
Powder, for solution	Intravenous	100 mg / vial
Powder, for solution	Intravenous	400 mg / vial
Injection	Parenteral
Injection	Parenteral	100 mg
Injection, powder, for solution	Intravenous	100 mg
Injection	Parenteral	400 mg
Injection, powder, for solution	Intravenous	400 mg
Injection, powder, lyophilized, for solution	Intravenous	100 mg
Injection, powder, lyophilized, for solution	Intravenous	400 mg
Injection, solution, concentrate	Intravenous	100 mg/1vial

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US7612182	No	2009-11-03	2027-08-01

Properties

State

Solid

Experimental Properties

Not Available

Targets

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Details1. Interleukin-6

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

Antibody

General Function

Interleukin-6 receptor binding

Specific Function

Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Inv...

Gene Name

IL6

Uniprot ID

P05231

Uniprot Name

Interleukin-6

Molecular Weight

23717.965 Da

References

1. van Zaanen HC, Koopmans RP, Aarden LA, Rensink HJ, Stouthard JM, Warnaar SO, Lokhorst HM, van Oers MH: Endogenous interleukin 6 production in multiple myeloma patients treated with chimeric monoclonal anti-IL6 antibodies indicates the existence of a positive feed-back loop. J Clin Invest. 1996 Sep 15;98(6):1441-8. [Article]

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Drug created at March 16, 2015 19:35 / Updated at June 03, 2022 07:24