Tocilizumab

Identification

Summary

Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA).

Brand Names
Actemra, RoActemra
Generic Name
Tocilizumab
DrugBank Accession Number
DB06273
Background

Tocilizumab is a recombinant humanized monoclonal antibody IL-6 receptor inhibitor used to treat inflammatory and autoimmune conditions.6 It was first described in the literature in 2003 when Chugai, a subsidiary of Roche began developing IL-6 inhibiting monoclonal antibodies.2 It is currently being investigated to treat severely ill patients with COVID-19.1,7,8

Tocilizumab was granted FDA approval on 8 January 2010.6

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db06273
Protein Chemical Formula
C6428H9976N1720O2018S42
Protein Average Weight
148000.0 Da
Sequences
>Tocilizumab light chain:
DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPS
RFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. US Patent US10323095B2: Antibody-fynomer conjugates [Link]
>Tocilizumab heavy chain:
QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTY
NPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPG
References:
  1. US Patent US10323095B2: Antibody-fynomer conjugates [Link]
Download FASTA Format
Synonyms
  • Atlizumab
  • Tocilizumab
External IDs
  • MRA
  • MSB-11456
  • MSB11456
  • R-1569
  • RG-1569
  • RHPM-1
  • RO-4877533

Pharmacology

Indication

Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions.6 Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index.6 Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity.6

Mechanism of action

Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts.6 IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin.4 IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation.4 Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation.6

TargetActionsOrganism
AInterleukin-6 receptor subunit alpha
inhibitor
antibody
Humans
Absorption

A 162mg subcutaneous dose given weekly has a Cmax of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL.5 A 162mg subcutaneous dose given every 2 weeks has a Cmax of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL.5 A 162mg subcutaneous dose given every 4 weeks has a Cmax of 154±42µg/mL and an AUC of 39216±14304µg*h/mL.5

Volume of distribution

In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L.6 In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L.6 In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L.6 In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L.6

Protein binding

Data regarding the serum protein binding of tocilizumab is not readily available.6

Metabolism

Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes.3

Route of elimination

Data regarding the exact route of elimination of monoclonal antibodies is not readily available.3,6

Half-life

The half life of tocilizumab is concentration dependent.6 The terminal half life in rheumatoid arthritis patients is 21.5 days.6 The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days.6

Clearance

The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h.6 Clearance is dose dependent and changes from non linear at low doses to linear at higher doses.6

Adverse Effects
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Toxicity

Data regarding overdoses of tocilizumab are not readily available.6 Patients experiencing an overdose may develop neutropenia.6 In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment.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
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Tocilizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Tocilizumab.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Tocilizumab.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Tocilizumab.
AcebutololThe metabolism of Acebutolol can be increased when combined with Tocilizumab.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Tocilizumab.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Tocilizumab.
AcetohexamideThe metabolism of Acetohexamide can be increased when combined with Tocilizumab.
Acetylsalicylic acidThe metabolism of Acetylsalicylic acid can be increased when combined with Tocilizumab.
AcyclovirThe metabolism of Acyclovir can be increased when combined with Tocilizumab.
Interactions
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Food Interactions
No interactions found.

Products

Products
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International/Other Brands
RoActemra
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ActemraSolution400 mg / 20 mLIntravenousHoffmann La Roche2010-05-26Not applicableCanada flag
ActemraInjection, solution, concentrate20 mg/1mLIntravenousGenentech, Inc.2010-01-08Not applicableUS flag
ActemraSolution162 mg / 0.9 mLSubcutaneousHoffmann La Roche2019-01-15Not applicableCanada flag
ActemraSolution80 mg / 4 mLIntravenousHoffmann La Roche2010-05-26Not applicableCanada flag
ActemraSolution200 mg / 10 mLIntravenousHoffmann La Roche2010-05-26Not applicableCanada flag
ActemraInjection, solution180 mg/1mLSubcutaneousGenentech, Inc.2013-10-21Not applicableUS flag
ActemraInjection, solution, concentrate20 mg/1mLIntravenousGenentech, Inc.2010-01-08Not applicableUS flag
ActemraSolution162 mg / 0.9 mLSubcutaneousHoffmann La Roche2014-05-30Not applicableCanada flag
ActemraInjection, solution, concentrate20 mg/1mLIntravenousGenentech, Inc.2010-01-08Not applicableUS flag
Actemra ACTPenInjection, solution180 mg/1mLSubcutaneousGenentech, Inc.2018-11-19Not applicableUS flag

Categories

ATC Codes
L04AC07 — Tocilizumab
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
  • Humans and other mammals

Chemical Identifiers

UNII
I031V2H011
CAS number
375823-41-9

References

General References
  1. Cellina M, Orsi M, Bombaci F, Sala M, Marino P, Oliva G: Favorable changes of CT findings in a patient with COVID-19 pneumonia after treatment with tocilizumab. Diagn Interv Imaging. 2020 Mar 31. pii: S2211-5684(20)30087-5. doi: 10.1016/j.diii.2020.03.010. [Article]
  2. Ding C, Jones G: Technology evaluation: MRA, Chugai. Curr Opin Mol Ther. 2003 Feb;5(1):64-9. [Article]
  3. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH: Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010 Aug;49(8):493-507. doi: 10.2165/11531280-000000000-00000. [Article]
  4. Tanaka T, Narazaki M, Kishimoto T: IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014 Sep 4;6(10):a016295. doi: 10.1101/cshperspect.a016295. [Article]
  5. Abdallah H, Hsu JC, Lu P, Fettner S, Zhang X, Douglass W, Bao M, Rowell L, Burmester GR, Kivitz A: Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA. J Clin Pharmacol. 2017 Apr;57(4):459-468. doi: 10.1002/jcph.826. Epub 2016 Nov 17. [Article]
  6. FDA Approved Drug Products: Actemra Tocilizumab Intravenous or Subcutaneous Injection [Link]
  7. Clinical Trials: TOCIVID-19 [Link]
  8. Clinical Trials: COVACTA [Link]
KEGG Drug
D02596
PubChem Substance
347910344
RxNav
612865
ChEMBL
CHEMBL1237022
PharmGKB
PA165292659
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tocilizumab
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
FDA label
Download (512 KB)
MSDS
Download (482 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentRheumatoid Arthritis2
4CompletedNot AvailableHealthy Volunteers1
4CompletedDevice FeasibilityRheumatoid Arthritis1
4CompletedOtherRheumatoid Arthritis1
4CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1
4CompletedTreatmentJuvenile Idiopathic Arthritis (JIA)1
4CompletedTreatmentRheumatoid Arthritis20
4CompletedTreatmentSchizoaffective Disorders / Schizophrenia1
4RecruitingTreatmentAdalimumab / Takayasu's Disease / Tocilizumab / Treatments1
4RecruitingTreatmentCommunity-acquired Pneumonia, Influenza, COVID-19 / Coronavirus Disease 2019 (COVID‑19)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous
Injection, solutionSubcutaneous180 mg/1mL
Injection, solution, concentrateIntravenous20 mg/1mL
SolutionIntravenous200 mg / 10 mL
SolutionIntravenous400 mg / 20 mL
SolutionIntravenous80 mg / 4 mL
SolutionSubcutaneous162 mg / 0.9 mL
Injection, solution162 mg/0.9mL
Injection, solutionSubcutaneous
Injection, solutionIntravenous
SolutionIntravenous80 mg
SolutionIntravenous400 mg
SolutionSubcutaneous162 mg
Injection, solutionParenteral; Subcutaneous
Injection, solutionSubcutaneous162 mg
Injection, solution, concentrateIntravenous
Injection, solution, concentrateIntravenous20 mg/ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2201781No2010-01-122015-06-07Canada flag
CA1341152No2000-12-122017-12-12Canada flag

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Antibody
General Function
Protein homodimerization activity
Specific Function
Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulati...
Gene Name
IL6R
Uniprot ID
P08887
Uniprot Name
Interleukin-6 receptor subunit alpha
Molecular Weight
51547.015 Da
References
  1. Smolen JS, Maini RN: Interleukin-6: a new therapeutic target. Arthritis Res Ther. 2006;8 Suppl 2:S5. Epub 2006 Jul 28. [Article]
  2. Betts BC, St Angelo ET, Kennedy M, Young JW: Anti-IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses. Blood. 2011 Nov 10;118(19):5340-3. doi: 10.1182/blood-2011-06-363390. Epub 2011 Sep 22. [Article]

Enzymes

Kind
Protein
Organism
Humans
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
References
  1. Long TJ, Cosgrove PA, Dunn RT 2nd, Stolz DB, Hamadeh H, Afshari C, McBride H, Griffith LG: Modeling Therapeutic Antibody-Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform. Drug Metab Dispos. 2016 Dec;44(12):1940-1948. doi: 10.1124/dmd.116.071456. Epub 2016 Sep 12. [Article]
  2. FDA Approved Drug Products: Actemra Tocilizumab Intravenous or Subcutaneous Injection [Link]

Drug created on March 19, 2008 16:20 / Updated on June 17, 2021 15:28