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

Protein Chemical Formula: C₆₄₂₈H₉₉₇₆N₁₇₂₀O₂₀₁₈S₄₂
Protein Average Weight: 148000.0 Da

Sequences

>Tocilizumab light chain:
DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPS
RFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

US Patent US10323095B2: Antibody-fynomer conjugates [Link]

>Tocilizumab heavy chain:
QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTY
NPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPG

References:

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

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Drug Discovery

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Associated Conditions

Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
AInterleukin-6 receptor subunit alpha	inhibitor antibody	Humans

Absorption

A 162mg subcutaneous dose given weekly has a C_max 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 C_max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL.⁵ A 162mg subcutaneous dose given every 4 weeks has a C_max 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.

Drug	Interaction
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Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Tocilizumab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Tocilizumab.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Tocilizumab.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Tocilizumab.
Acebutolol	The metabolism of Acebutolol can be increased when combined with Tocilizumab.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Tocilizumab.
Acetaminophen	The metabolism of Acetaminophen can be increased when combined with Tocilizumab.
Acetohexamide	The metabolism of Acetohexamide can be increased when combined with Tocilizumab.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be increased when combined with Tocilizumab.
Acyclovir	The metabolism of Acyclovir can be increased when combined with Tocilizumab.

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Food Interactions

No interactions found.

Products

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International/Other Brands

RoActemra

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Actemra	Injection, solution, concentrate	20 mg/1mL	Intravenous	Genentech, Inc.	2010-01-08	Not applicable
Actemra	Solution	162 mg / 0.9 mL	Subcutaneous	Hoffmann La Roche	2014-05-30	Not applicable
Actemra	Injection, solution, concentrate	20 mg/1mL	Intravenous	Genentech, Inc.	2010-01-08	Not applicable
Actemra	Solution	400 mg / 20 mL	Intravenous	Hoffmann La Roche	2010-05-26	Not applicable
Actemra	Injection, solution	180 mg/1mL	Subcutaneous	Genentech, Inc.	2013-10-21	Not applicable
Actemra	Injection, solution, concentrate	20 mg/1mL	Intravenous	Genentech, Inc.	2010-01-08	Not applicable
Actemra	Solution	162 mg / 0.9 mL	Subcutaneous	Hoffmann La Roche	2019-01-15	Not applicable
Actemra	Solution	200 mg / 10 mL	Intravenous	Hoffmann La Roche	2010-05-26	Not applicable
Actemra	Solution	80 mg / 4 mL	Intravenous	Hoffmann La Roche	2010-05-26	Not applicable
Actemra ACTPen	Injection, solution	180 mg/1mL	Subcutaneous	Genentech, Inc.	2018-11-19	Not applicable

Chemical Identifiers

UNII: I031V2H011
CAS number: 375823-41-9

References

General References

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]
Ding C, Jones G: Technology evaluation: MRA, Chugai. Curr Opin Mol Ther. 2003 Feb;5(1):64-9. [Article]
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]
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]
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]
FDA Approved Drug Products: Actemra Tocilizumab Intravenous or Subcutaneous Injection [Link]
Clinical Trials: TOCIVID-19 [Link]
Clinical Trials: COVACTA [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Rheumatoid Arthritis	2
4	Completed	Not Available	Healthy Volunteers	1
4	Completed	Device Feasibility	Rheumatoid Arthritis	1
4	Completed	Other	Rheumatoid Arthritis	1
4	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
4	Completed	Treatment	Juvenile Idiopathic Arthritis (JIA)	1
4	Completed	Treatment	Rheumatoid Arthritis	20
4	Completed	Treatment	Schizoaffective Disorders / Schizophrenia	1
4	Recruiting	Treatment	Adalimumab / Takayasu's Disease / Tocilizumab / Treatments	1
4	Recruiting	Treatment	Community-acquired Pneumonia, Influenza, COVID-19 / Coronavirus Disease 2019 (COVID‑19)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous
Injection, solution	Subcutaneous	180 mg/1mL
Injection, solution, concentrate	Intravenous	20 mg/1mL
Solution	Intravenous	200 mg / 10 mL
Solution	Intravenous	400 mg / 20 mL
Solution	Intravenous	80 mg / 4 mL
Solution	Subcutaneous	162 mg / 0.9 mL
Injection, solution		162 mg/0.9mL
Injection, solution	Subcutaneous
Injection, solution	Intravenous
Solution	Intravenous	80 mg
Solution	Intravenous	400 mg
Solution	Subcutaneous	162 mg
Injection, solution	Parenteral; Subcutaneous
Injection, solution	Subcutaneous	162 mg
Injection, solution, concentrate	Intravenous
Injection, solution, concentrate	Intravenous	20 mg/ml

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2201781	No	2010-01-12	2015-06-07
CA1341152	No	2000-12-12	2017-12-12

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Interleukin-6 receptor subunit alpha

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

Smolen JS, Maini RN: Interleukin-6: a new therapeutic target. Arthritis Res Ther. 2006;8 Suppl 2:S5. Epub 2006 Jul 28. [Article]
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

Details1. Cytochrome P450 3A4

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

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]
FDA Approved Drug Products: Actemra Tocilizumab Intravenous or Subcutaneous Injection [Link]

Drug created on March 19, 2008 16:20 / Updated on June 23, 2021 06:09

Tocilizumab

Identification

References:

References:

Pharmacology

Interactions

Products

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Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

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References

Enzymes

References