Identification

Name
Tocilizumab
Accession Number
DB06273
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Tocilizumab is a recombinant, humanized, anti-human interleukin 6 (IL-6) receptor monoclonal antibody that achieves a significant therapeutic response rate. The light chain is made up of 214 amino acids. The heavy chain is made up of 448 amino acids. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. FDA approved on January 8, 2010.

Tocilizumab (injection) was further approved by the FDA for the treatment of adults with giant cell arteritis, an inflammation of the blood vessels (vasculitis) in May, 2017. In a double-blind, placebo-controlled study, the patients achieved sustained remission from Week 12 through Week 52, which was associated with significant improvements in symptoms of giant cell arteritis, normalization of inflammatory laboratory tests and tapering the use of corticosteroids [2].

Protein structure
Db06273
Protein chemical formula
C6428H9976N1720O2018S42
Protein average weight
148000.0 Da
Sequences
Not Available
Synonyms
  • Atlizumab
External IDs
MRA / R-1569 / RHPM-1 / RO-4877533
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ActemraSolution162 mgSubcutaneousHoffmann La Roche2014-05-30Not applicableCanada
ActemraSolution80 mgIntravenousHoffmann La Roche2010-05-26Not applicableCanada
ActemraInjection, solution, concentrate20 mg/1mLIntravenousGenentech, Inc.2010-01-08Not applicableUs
ActemraSolution400 mgIntravenousHoffmann La Roche2010-05-26Not applicableCanada
ActemraInjection, solution180 mg/1mLSubcutaneousGenentech, Inc.2013-10-21Not applicableUs
ActemraInjection, solution, concentrate20 mg/1mLIntravenousGenentech, Inc.2010-01-08Not applicableUs
ActemraSolution200 mgIntravenousHoffmann La Roche2010-05-26Not applicableCanada
ActemraInjection, solution, concentrate20 mg/1mLIntravenousGenentech, Inc.2010-01-08Not applicableUs
International/Other Brands
RoActemra
Categories
UNII
I031V2H011
CAS number
375823-41-9

Pharmacology

Indication

Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). It is also indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) and active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older.

Associated Conditions
Pharmacodynamics

A decrease in C-reactive protein (CRP) was noted as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with both doses, however the greatest improvements were observed with 8 mg per kg tocilizumab. Similar pharmacodynamic changes were also observed in active polyarticular juvenile idiopathic arthritis and active systemic juvenile idiopathic arthritis patients.

Mechanism of action

Interleukin (IL)-6 plays essential roles not only in the immune response, but also in haematopoiesis and the central nervous system. Unregulated production of IL-6 has been found in chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (soJIA), Crohn's disease (CD), systemic lupus erythematosus (SLE) and vasculitis. Furthermore, IL-6 activities can explain many symptoms of these diseases. More importantly, serum levels of IL-6 are correlated with disease activity. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors.

TargetActionsOrganism
AInterleukin-6 receptor subunit alpha
antibody
Human
Absorption

When 4 mg/kg of tocilizumab was given every 4 weeks to RA patients, the pharmacokinetic parameters at steady state are as follows: AUC = 13000 ± 5800 mcg∙h/mL; Cmax = 88.3 ± 41.4 mcg/mL. Tocilizumab accumulates following repeated doses. Furthermore, an increased body weight may increase plasma levels of tocilizumab.

When a dose of 8 mg/kg of tocilizumab is given to PJIA patients, the pharmacokinetic parameters are as follows: AUC = 29500 ± 8660 mcg∙h/mL; Cmax = 182 ± 37 mcg/mL.

When a dose of 8 mg/kg of tocilizumab is given to SJIA patients, the pharmacokinetic parameters are as follows: AUC = 32200 ± 9960 mcg∙h/mL; Cmax = 245 ± 57.2 mcg/mL.

Volume of distribution

In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.

In pediatric patients with SJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.

Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation.

Half life

The half-life of tocilizumab is concentration-dependent. The concentration-dependent apparent half-life is up to 11 days for 4 mg/kg and up to 13 days for 8 mg/kg every 4 weeks in patients with RA at steady-state. The half-life in children with PJIA is up to 16 days. The half-life in pediatric patients with SJIA is up to 23 days.

Clearance

The clearance of tocilizumab decreases with increasing dose. At the 10 mg/kg single dose in RA patients, mean clearance was 0.29 ± 0.10 mL/hr/kg. The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. At low concentrations, concentration-dependent nonlinear clearance is dominant. At high concentrations, linear clearance dominates. The estimated linear clearances for specific patient populations are as follows: RA = 12.5 mL/h; PJIA, pediatric patients = 5.8 mL/h; SJIA, pediatric patients = 7.1 mL/h.

Toxicity

Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Tocilizumab.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Tocilizumab.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Tocilizumab.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Tocilizumab.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Tocilizumab.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Tocilizumab.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Tocilizumab.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Tocilizumab is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
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.
Food Interactions
Not Available

References

General References
  1. Mihara M, Nishimoto N, Ohsugi Y: The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin Biol Ther. 2005 May;5(5):683-90. [PubMed:15934843]
  2. FDA Press Announcements: FDA approves first drug to specifically treat giant cell arteritis [Link]
External Links
KEGG Drug
D02596
PubChem Substance
347910344
ChEMBL
CHEMBL1237022
PharmGKB
PA165292659
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tocilizumab
ATC Codes
L04AC07 — Tocilizumab
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
FDA label
Download (512 KB)
MSDS
Download (482 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0WithdrawnTreatmentMultiple Myeloma (MM) / Myeloma-Multiple1
1Active Not RecruitingTreatmentJuvenile Idiopathic Arthritis (JIA)1
1CompletedBasic ScienceRheumatoid Arthritis1
1CompletedTreatmentB-Cell Chronic Lymphocytic Leukemia / Chronic Lymphocytic Leukaemia (CLL)1
1CompletedTreatmentCastleman's Disease1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentJuvenile Idiopathic Arthritis (JIA)2
1CompletedTreatmentJuvenile Idiopathic Arthritis (JIA) / Juvenile Idiopathic Arthritis, Rheumatoid Arthritis / Systemic Juvenile Idiopathic Arthritis (SJIA)1
1CompletedTreatmentRheumatoid Arthritis3
1CompletedTreatmentSchizophrenic Disorders1
1RecruitingTreatmentB-cell Non-Hodgkin's Lymphomas1
1RecruitingTreatmentCancer, Breast1
1RecruitingTreatmentChronic Leukemias / Leukemia, Acute / Malignant Lymphomas / Multiple Myeloma (MM) / Myelodysplastic Syndromes1
1RecruitingTreatmentFollicular Lymphoma (FL) / Lymphoma, B-Cell / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentPharmacokinetics1
1RecruitingTreatmentPsychotic Disorder NOS / Schizophrenic Disorders1
1RecruitingTreatmentRheumatoid Arthritis1
1TerminatedTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2Active Not RecruitingBasic ScienceHuman Immunodeficiency Virus (HIV) Infections1
1, 2Active Not RecruitingTreatmentDiffuse posterior uveitis / Non-infectious Intermediate, Posterior, or Pan-uveitis / Pan-uveitis / Uveitis, Intermediate1
1, 2CompletedTreatmentEnd Stage Renal Disease (ESRD)1
1, 2CompletedTreatmentNeuromyelitis Optica / Neuromyelitis Optica Spectrum Disorders1
1, 2CompletedTreatmentRecurrent Ovarian Cancer1
1, 2Not Yet RecruitingTreatmentHepatocellular,Carcinoma1
1, 2RecruitingPreventionCytokine Release Syndrome / Stem Cell Transplant Complications1
1, 2RecruitingTreatmentAcute Lymphocytic Leukemia, Pediatric / B-cell Acute Lymphoblastic Leukemia1
1, 2RecruitingTreatmentB-cell Non-Hodgkin's Lymphomas1
1, 2RecruitingTreatmentChronic Subdural Hematomas1
1, 2RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
1, 2TerminatedTreatmentGraft Versus Host Disease, Acute1
1, 2TerminatedTreatmentJuvenile Idiopathic Arthritis Associated Uveitis1
2Active Not RecruitingTreatmentDiabetes, Diabetes Mellitus Type 1 / New-onset Type 1 Diabetes Mellitus / T1D / T1DM1
2Active Not RecruitingTreatmentLate Complication From Kidney Transplant1
2CompletedPreventionAcute Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation / Hematopoietic Stem Cell Transplantation (HSCT)1
2CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS) / Lou Gehrig's Disease / Motor Neurone Disease1
2CompletedTreatmentGiant Cells Arteritis2
2CompletedTreatmentNon-ST Elevation Myocardial Infarction1
2CompletedTreatmentPolymyalgia Rheumatica (PMR)1
2CompletedTreatmentPulmonary Arterial Hypertension (PAH)1
2CompletedTreatmentRheumatoid Arthritis5
2Not Yet RecruitingTreatmentAutoimmune Diseases / Inflammatory Diseases1
2Not Yet RecruitingTreatmentCardiac Transplant1
2Not Yet RecruitingTreatmentMalignancies, Hematologic1
2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Leukemia Acute Myeloid Leukemia (AML) / Leukemia, Acute / Leukemias / Lymphoma, Hodgkins / Myelodysplastic Syndromes / Myelodysplastic-Myeloproliferative Diseases / Myeloproliferative Disorders / Non Hodgkin Lymphoma (NHL)1
2RecruitingTreatmentBehcet's Syndrome / Uveitis1
2RecruitingTreatmentBiotherapy / Uveitis1
2RecruitingTreatmentCastleman's Disease / Giant Lymph Node Hyperplasia1
2RecruitingTreatmentCoronary Heart Disease (CHD) / Myocardial Infarction1
2RecruitingTreatmentDermatomyositis / Polymyositis1
2RecruitingTreatmentFamilial Mediterranean Fever (FMF )1
2RecruitingTreatmentLeukemias1
2RecruitingTreatmentLymphohistiocytosis, Hemophagocytic1
2RecruitingTreatmentMajor Depressive Disorder (MDD)1
2RecruitingTreatmentSchnitzler's Syndrome1
2RecruitingTreatmentUnresectable Pancreatic Carcinoma1
2TerminatedTreatmentBehcet's Syndrome1
2TerminatedTreatmentErdheim-Chester Disease (ECD)1
2TerminatedTreatmentGlucocorticosteroid Refractory Acute GVHD1
2TerminatedTreatmentRheumatoid Arthritis1
2Unknown StatusTreatmentAdult's Still Disease1
2Unknown StatusTreatmentFibrous Dysplasia of Bone1
2WithdrawnSupportive CareGraft Versus Host Disease (GVHD)1
2WithdrawnTreatmentDiabetic Macular Edema (DME)1
2WithdrawnTreatmentRelapsing Polychondritis1
2, 3Active Not RecruitingTreatmentNeuromyelitis Optica / Neuromyelitis Optica Spectrum Disorders1
2, 3RecruitingTreatmentPrimary Sjögren's Syndrome (pSS)1
3Active Not RecruitingTreatmentGiant Cells Arteritis1
3Active Not RecruitingTreatmentSclerosis, Progressive Systemic1
3CompletedTreatmentGraves´ Ophthalmopathy / Thyroid Associated Ophthalmopathy / Thyroid Eye Disease1
3CompletedTreatmentJuvenile Idiopathic Arthritis (JIA)5
3CompletedTreatmentPolyarticular Juvenile Idiopathic Arthritis1
3CompletedTreatmentRheumatoid Arthritis67
3CompletedTreatmentSclerosis, Progressive Systemic1
3CompletedTreatmentSystemic Juvenile Idiopathic Arthritis (SJIA)3
3RecruitingSupportive CarePolymyalgia Rheumatica1
3RecruitingTreatmentGiant Cells Arteritis1
3RecruitingTreatmentJuvenile Idiopathic Arthritis (JIA)1
3RecruitingTreatmentOsteoarthritis of the Hands1
3RecruitingTreatmentPolymyalgia Rheumatica1
3RecruitingTreatmentRheumatoid Arthritis2
3RecruitingTreatmentTakayasu's Disease1
3TerminatedTreatmentAnkylosing Spondylitis (AS)2
3TerminatedTreatmentJuvenile Idiopathic Arthritis (JIA)1
3TerminatedTreatmentRheumatoid Arthritis1
4Active Not RecruitingTreatmentJuvenile Idiopathic Arthritis (JIA)1
4Active Not RecruitingTreatmentRheumatoid Arthritis1
4CompletedNot AvailableHealthy Volunteers1
4CompletedDevice FeasibilityRheumatoid Arthritis1
4CompletedOtherRheumatoid Arthritis1
4CompletedTreatmentCardiovascular Disease, Rheumatoid Arthritis / Rheumatoid Arthritis1
4CompletedTreatmentRheumatoid Arthritis16
4CompletedTreatmentSchizoaffective Disorders / Schizophrenic Disorders1
4Enrolling by InvitationTreatmentRheumatoid Arthritis1
4Not Yet RecruitingTreatmentGiant Cells Arteritis1
4RecruitingBasic ScienceRheumatoid Arthritis1
4RecruitingTreatmentGiant Cells Arteritis1
4RecruitingTreatmentJuvenile Idiopathic Arthritis (JIA)1
4RecruitingTreatmentRheumatoid Arthritis6
4TerminatedTreatmentRheumatoid Arthritis3
4WithdrawnTreatmentRheumatoid Arthritis1
Not AvailableActive Not RecruitingNot AvailableRheumatoid Arthritis2
Not AvailableCompletedNot AvailablePolymyalgia Rheumatica1
Not AvailableCompletedNot AvailablePsoriatic Arthritis / Rheumatoid Arthritis / Spondyloarthritis1
Not AvailableCompletedNot AvailableRheumatoid Arthritis16
Not AvailableCompletedPreventionBMI >30 kg/m2 / Type 2 Diabetes Mellitus1
Not AvailableCompletedTreatmentMyocardial Infarction1
Not AvailableCompletedTreatmentRelapsing Polychondritis1
Not AvailableCompletedTreatmentRheumatoid Arthritis3
Not AvailableNo Longer AvailableNot AvailableJuvenile Idiopathic Arthritis (JIA)1
Not AvailableNot Yet RecruitingNot AvailableRheumatoid Arthritis1
Not AvailableNot Yet RecruitingTreatmentArthritis / Colitis / Tumors, Solid1
Not AvailableRecruitingNot AvailableAnkylosing Spondylitis (AS) / Psoriatic Arthritis / Rheumatoid Arthritis1
Not AvailableRecruitingNot AvailableInflammatory Reaction / Rheumatoid Arthritis1
Not AvailableRecruitingNot AvailableRheumatoid Arthritis4
Not AvailableRecruitingOtherAdiposity1
Not AvailableRecruitingTreatmentLymphoblastic Leukemia, Acute, Childhood1
Not AvailableTerminatedTreatmentRheumatoid Arthritis, Juvenile / Still's Disease, Juvenile Onset1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous180 mg/1mL
Injection, solution, concentrateIntravenous20 mg/1mL
SolutionIntravenous200 mg
SolutionIntravenous400 mg
SolutionIntravenous80 mg
SolutionSubcutaneous162 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2201781No2010-01-122015-06-07Canada
CA1341152No2000-12-122017-12-12Canada

Properties

State
Liquid
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
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. [PubMed:16899109]

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 19, 2008 10:20 / Updated on November 14, 2018 12:54