Siltuximab

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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		••••••••••••		••••• ••••••••••••• ••••••••• ••• ••••••••	•••••••••

Contraindications & Blackbox Warnings

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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

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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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
Sylvant	Injection, powder, for solution	400 mg	Intravenous	Recordati Netherlands B.V.	2020-12-23	Not applicable
Sylvant	Powder, for solution	400 mg / vial	Intravenous	Recordati Rare Diseases Canada Inc	2015-03-03	Not applicable
Sylvant	Injection, powder, lyophilized, for solution	400 mg/1	Intravenous	Janssen Biotech, Inc.	2014-04-01	2021-01-31
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	RECORDATI RARE DISEASES, INC.	2014-04-23	Not applicable

Chemical Identifiers

UNII: T4H8FMA7IM
CAS number: 541502-14-1

References

General References

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]
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]
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 Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
3	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	1	somestatus	stop reason	just information to hide
3	Terminated	Treatment	Acute Respiratory Distress Syndrome (ARDS) / Coronavirus Disease 2019 (COVID‑19) / Lung Disorder / Pneumonia / Respiratory Tract Diseases / Respiratory Tract Infections (RTI)	1	somestatus	stop reason	just information to hide
3	Withdrawn	Treatment	Multiple Myeloma (MM)	1	somestatus	stop reason	just information to hide
2	Active Not Recruiting	Treatment	Multiple Myeloma (MM) / Primary Amyloidosis	1	somestatus	stop reason	just information to hide
2	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	1	somestatus	stop reason	just information to hide

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: Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. Binds to IL6R, then the complex associates to the signaling subunit IL6ST/gp130 to trigger the intracellular IL6-signaling pathway (Probable). The interaction with the membrane-bound IL6R and IL6ST stimulates 'classic signaling', whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable)
Specific Function: Cytokine activity
Gene Name: IL6
Uniprot ID: P05231
Uniprot Name: Interleukin-6
Molecular Weight: 23717.965 Da

References

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]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inducer

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

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

Siltuximab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Targets

References

Enzymes