Identification

Name
Siltuximab
Accession Number
DB09036
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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.

Protein structure
Db09036
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
Not Available
External IDs
CLLB8 / CNTO 328 / CNTO-328 / CNTO328
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SylvantPowder, for solution400 mgIntravenousJanssen Pharmaceuticals2015-03-03Not applicableCanada
SylvantInjection, powder, lyophilized, for solution100 mg/1IntravenousJanssen Biotech, Inc.2014-04-23Not applicableUs
SylvantPowder, for solution100 mgIntravenousJanssen Pharmaceuticals2015-03-03Not applicableCanada
SylvantInjection, powder, lyophilized, for solution400 mg/1IntravenousJanssen Biotech, Inc.2014-04-01Not applicableUs
Categories
UNII
T4H8FMA7IM
CAS number
541502-14-1

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.

Associated Conditions
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.

TargetActionsOrganism
AInterleukin-6
antagonist
antibody
Human
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.

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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Siltuximab.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Siltuximab.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Siltuximab.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Siltuximab.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Siltuximab.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be increased when combined with Siltuximab.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Siltuximab.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Siltuximab.
7-ethyl-10-hydroxycamptothecinThe metabolism of 7-ethyl-10-hydroxycamptothecin can be increased when combined with Siltuximab.
8-azaguanineThe metabolism of 8-azaguanine can be increased when combined with Siltuximab.
Food Interactions
Not Available

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. [PubMed:20179212]
  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. [PubMed:25601959]
  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. [PubMed:25110138]
External Links
KEGG Drug
D09669
PubChem Substance
347910394
ChEMBL
CHEMBL1743070
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Siltuximab
ATC Codes
L04AC11 — Siltuximab
AHFS Codes
  • 92:44.00 — Immunosuppressive Agents
FDA label
Download (326 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceDiabetes, Diabetes Mellitus Type 11
0WithdrawnTreatmentAgnogenic Myeloid Metaplasia / Polycythemia Vera (PV) / Primary Myelofibrosis / Thrombocytopenias1
1CompletedTreatmentGiant Lymph Node Hyperplasia / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentMonoclonal Gammopathy of Undetermined Significance (MGUS) / Multiple Myeloma (MM) / Plasma Cell Neoplasms1
1CompletedTreatmentProstatic Neoplasms1
1TerminatedTreatmentMultiple Myeloma (MM)1
1, 2CompletedTreatmentNeoplasms, Colorectal / Neoplasms, Head and Neck / Neoplasms, Lung / Neoplasms, Ovarian / Neoplasms, Pancreatic1
1, 2CompletedTreatmentPlasma Cell Myeloma1
1, 2CompletedTreatmentRenal Cell Adenocarcinoma1
1, 2RecruitingTreatmentPsychotic Disorder NOS / Schizophrenic Disorders1
2Active Not RecruitingTreatmentHigh-risk Smoldering Multiple Myeloma1
2Active Not RecruitingTreatmentMultiple Myeloma (MM)1
2CompletedTreatmentMulticentric Castleman's Disease2
2CompletedTreatmentMultiple Myeloma (MM)2
2CompletedTreatmentProstate Cancer1
2RecruitingTreatmentAL Amyloidosis / Multiple Myeloma (MM)1
2TerminatedTreatmentMyelodysplastic Syndrome1
2TerminatedTreatmentProstate Cancer1
2WithdrawnTreatmentRenal Cancers1
3WithdrawnTreatmentMultiple Myeloma (MM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous100 mg/1
Injection, powder, lyophilized, for solutionIntravenous400 mg/1
Powder, for solutionIntravenous100 mg
Powder, for solutionIntravenous400 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7612182No2009-11-032027-08-01Us

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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. [PubMed:8823310]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Drug created on March 16, 2015 13:35 / Updated on December 18, 2018 05:46