Infliximab

Identification

Name
Infliximab
Accession Number
DB00065
Description

Infliximab is a tumor necrosis factor (TNF-alpha or TNF-α) blocker and a chimeric monoclonal IgG1 antibody composed of human constant (75%) and murine variable (25%) regions 3. Infliximab is produced by a recombinant cell line cultured by continuous perfusion. Tumor necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine involved in chronic inflammatory diseases 3. Its hyperactivity and enhanced signalling pathways can be observed in inflammatory diseases where it activates further pro-inflammatory cascades. By binding to both the soluble subunit and the membrane-bound precursor of TNF-α 1, infliximab disrupts the interaction of TNF-α with its receptors and may also cause lysis of cells that produce TNF-α 1.

Infliximab was first approved by the FDA in 1998 under the market name Remicade as an intravenous injection. It is indicated for the treatment of various inflammatory disorders such as adult or pediatric Chron's disease, adult or pediatric ulcerative colitis, rheumatoid arthritis in combination with methotrexate, ankylosing spondyliti, psoriatic arthritis, and plaque psoriasis Label. In clinical trials, multiple infusions of infliximab displayed in a reduction of signs and symptoms of inflammatory diseases and induction of remission in patients who have had an inadequate response to alternative first-line therapies for that disorder Label.

There are currently two biosilimars of infliximab available in the US market that demonstrate a high degree of similarity to the reference product, Remicade. They are approved for all eligible indications of the reference product. Inflectra, a first biosimilar drug product, was approved in 2016. In December 2017, Ixifi, a second biosimilar that was developed by Pfizer, was granted approval by the FDA.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db00065
Protein Chemical Formula
C6428H9912N1694O1987S46
Protein Average Weight
144190.3 Da
Sequences
Not Available
Synonyms
  • Infliximab (genetical recombination)
  • Infliximab-abda
  • Infliximab-axxq
  • Infliximab-dyyb
  • Infliximab-qbtx
External IDs
  • ABP 710
  • ABP-710
  • BOW-015
  • BOW015
  • CT-P-13
  • CT-P13
  • GP 1111
  • GP-1111
  • PF-06438179
  • TA-650

Pharmacology

Indication
  • Indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult or pediatric (≥ 6 years of age) patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy
  • Indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
  • Indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult or pediatric (≥ 6 years of age) patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
  • Indicated for, in combination with methotrexate, reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
  • Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
  • Indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
  • Indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.
Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Infliximab disrupts the activation of pro-inflammaory cascade signalling. Infliximab has shown to reduce infiltration of inflammatory cells into sites of inflammation. It also attenautes the expression of molecules mediating cellular adhesion {including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)}, chemoattraction {[IL-8 and monocyte chemotactic protein (MCP-1)} and tissue degradation {matrix metalloproteinase (MMP) 1 and 3} Label.

Mechanism of action

Infliximab is a IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory cascade signalling. Binding of the antibody to TNF-α prevents TNF-α from interacting with its receptors. Infliximab does not neutralize TNF-β (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNF-α Label. Blocked actions of TNF-α further leads to downregulation of local and systemic pro-inflammatory cytokines (i.e. IL-1, IL-6), reduction of lymphocyte and leukocyte migration to sites of inflammation, induction of apoptosis of TNF-producing cells (i.e. activated monocytes and T lymphocytes), increased levels of nuclear factor-κB inhibitor, and reduction of reduction of endothelial adhesion molecules and acute phase proteins 3. Its inhibitory actions on TNF-α was demonstrated in human fibroblasts, endothelial cells, neutrophils, B and Tlymphocytes and epithelial cells Label. Infliximab also atteunates the production of tissue degrading enzymes synthesized by synoviocytes and/or chondrocytes. According to a transgenic mice study that developed polyarthritis due to consitutive levels of human TNF-α, infliximab decreased synovitis and joint erosions in collagen-induced arthritis and allows eroded joints to heal Label.

TargetActionsOrganism
ATumor necrosis factor
inhibitor
Humans
Absorption

Following a single intravenous infusion, infliximab absorption displays a linear relationship between the dose administered and the maximum serum concentration Label.

In patients with Crohn's disease, the maximum plasma concentration (Cmax) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 75 µg/mL and 181 µg/mL, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Cmax of 120 µg/mL and 189 µg/mL , respectively 3.

In patients with rheumatoid arthritis, the Cmax of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 192±51 µg/mL, 427±106 µg/mL, and 907±183 µg/mL, respectively 3.

Volume of distribution

Based on a pharmacokinetic study of adult patients, the distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment Label.

In patients with Crohn's disease, the apparent volume of distribution at steady state (Vss) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 80 mL/kg and 65 mL/kg, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Vss of 70 mL/kg and 81 mL/kg , respectively 3.

In patients with rheumatoid arthritis, the Vss of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 4.3±2.5 L, 3.2±0.7 L, and 3.1±0.6 L, respectively 3.

Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Therapeutic monoclonal antibodies including infliximab are predicted to be nonspecifically metabolized to peptides and amino acids that can be re-used in the body for de novo synthesis of proteins or arc excreted by the kidney 4. The reticuloendothelial system (RES) are phagocytic cells of the immune system such as macrophages and monocytes that play a role in the elimination of endogenous IgG antibodies. Although administered infliximab accounts for a small fraction of total endogenous IgG and this route is not likely saturated by therapeutic mAbs, infliximab may be removed by opsonization via RES following binding of the Fc part of the antibody to Fcy-receptors expressed on the RES 4.

Half-life

The median terminal half-life of infliximab is 7.7 to 9.5 days. The data is based on a pharmacokinetic study in patients with Crohn's disease, plaque psoriasis and rheumatoid arthritis receiving a single dose of infliximab Label.

Clearance

In patients with Crohn's disease, the total body clearance (CL) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 18.4 mL/h and 14.3 mL/h, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in CL of 15.2 mL/h and 15.2 mL/h, respectively 3.

In patients with rheumatoid arthritis, the CL of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 11±7.5 mL/h, 11.4±5 mL/h, and 11±8.9 mL/h, respectively 3.

Development of antibodies to infliximab increased infliximab clearance Label.

Adverse Effects
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Toxicity

In an acute toxicity animal study, the NOAEL of intravenous infliximab in rats was 50 mg/kg. In a repeated dose animal study, the NOAEL values of intravenous infliximab was 50 mg/kg in rats at 2 weeks following 3 doses and 40 mg/kg/day in mice at 6 months MSDS.

The toxicological potential of infliximab in humans has not yet been fully established. According to an analogous antibody study, infliximab is not predicted to induce tumorigenic, clastogenic or mutagenic effects. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study Label.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Low affinity immunoglobulin gamma Fc region receptor III-A---(C;C)CC Allele (homozygous)Effect Directly StudiedPatients with this genotype have increased ACR20 response when using infliximab to treat rheumatoid arthritis.Details

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 infection can be increased when Infliximab is combined with Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Infliximab.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Infliximab.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Infliximab.
AcebutololThe metabolism of Acebutolol can be increased when combined with Infliximab.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Infliximab.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Infliximab.
AcetohexamideThe metabolism of Acetohexamide can be increased when combined with Infliximab.
Acetylsalicylic acidThe metabolism of Acetylsalicylic acid can be increased when combined with Infliximab.
AcipimoxThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Infliximab is combined with Acipimox.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

Products

International/Other Brands
Avsola (Amgen)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AvsolaPowder, for solution100 mgIntravenousAmgen2020-06-01Not applicableCanada flag
AvsolaInjection, powder, lyophilized, for solution100 mg/10mLIntravenousAMGEN INC2019-12-12Not applicableUS flag
FlixabiInjection, powder, for solution100 mgIntravenousSamsung Bioepis Uk Limited (Sbuk)2016-05-26Not applicableEU flag
FlixabiInjection, powder, for solution100 mgIntravenousSamsung Bioepis Uk Limited (Sbuk)2016-05-26Not applicableEU flag
FlixabiInjection, powder, for solution100 mgIntravenousSamsung Bioepis Uk Limited (Sbuk)2016-05-26Not applicableEU flag
FlixabiInjection, powder, for solution100 mgIntravenousSamsung Bioepis Uk Limited (Sbuk)2016-05-26Not applicableEU flag
FlixabiInjection, powder, for solution100 mgIntravenousSamsung Bioepis Uk Limited (Sbuk)2016-05-26Not applicableEU flag
InflectraInjection, powder, for solution100 mgIntravenousPfizer Europe Ma Eeig2013-09-10Not applicableEU flag
InflectraInjection, powder, lyophilized, for solution100 mg/10mLIntravenousPfizer Laboratories Div Pfizer Inc2016-11-21Not applicableUS flag
InflectraInjection, powder, for solution100 mgIntravenousPfizer Europe Ma Eeig2013-09-10Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L04AB02 — Infliximab
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

Chemical Identifiers

UNII
B72HH48FLU
CAS number
170277-31-3

References

General References
  1. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ: Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999 May 6;340(18):1398-405. [PubMed:10228190]
  2. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ: Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004 Feb 26;350(9):876-85. [PubMed:14985485]
  3. Klotz U, Teml A, Schwab M: Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet. 2007;46(8):645-60. doi: 10.2165/00003088-200746080-00002. [PubMed:17655372]
  4. 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. [PubMed:20608753]
  5. Link [Link]
  6. Link [Link]
  7. FDA Label: INFLECTRA (infliximab-dyyb) for Injection, for Intravenous Use [Link]
  8. FDA Label: IXIFI (infliximab-qbtx) for injection, for Intravenous Use [Link]
UniProt
P01857
Genbank
J00228
PubChem Substance
46505602
RxNav
1790539
ChEMBL
CHEMBL1201581
Therapeutic Targets Database
DAP000107
PharmGKB
PA452639
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Infliximab
AHFS Codes
  • 92:36.00 — Disease-modifying Antirheumatic Agents
FDA label
Download (1.21 MB)
MSDS
Download (39.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingBasic ScienceRheumatoid Arthritis1
4Active Not RecruitingTreatmentCrohn's Disease (CD)2
4Active Not RecruitingTreatmentInfliximab / Uveitis1
4Active Not RecruitingTreatmentRheumatoid Arthritis1
4CompletedNot AvailableAnkylosing Spondylitis (AS) / Crohn's Disease (CD)1
4CompletedNot AvailableAnkylosing Spondylitis (AS) / Psoriasis / Psoriatic Arthritis / Rheumatoid Arthritis1
4CompletedNot AvailableCrohn's Disease (CD) / Psoriasis / Rheumatoid Arthritis1
4CompletedNot AvailableRheumatoid Arthritis2
4CompletedDiagnosticAnkylosing Spondylitis (AS)1
4CompletedOtherHepatosplenic T-Cell Lymphoma1

Pharmacoeconomics

Manufacturers
  • J&J and Mitsubisi Tanabe
Packagers
  • Centocor Ortho Biotech Inc.
  • Hospira Inc.
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous100 mg
PowderParenteral100 MG
Injection, powder, lyophilized, for solutionIntravenous100 mg/10mL
PowderIntravenous; Parenteral100 MG
Injection, powder, lyophilized, for solutionIntravenous100 mg
Injection, powder, for solutionIntravenous; Parenteral100 MG
Injection, solutionCutaneous120 MG
Powder, for solutionIntravenous
InjectionIntravenous100 mg
Injection, powder, lyophilized, for solutionIntravenous100 mg/1
Powder, for solutionIntravenous100 mg
Prices
Unit descriptionCostUnit
Remicade 100 mg Solution Vial821.02USD vial
Remicade 100 mg vial789.44USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2106299No2001-02-062012-03-18Canada flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)61 °C (FAB fragment), 71 °C (whole mAb)Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)
hydrophobicity-0.441Not Available
isoelectric point8.25Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Tumor necrosis factor receptor binding
Specific Function
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct ac...
Gene Name
TNF
Uniprot ID
P01375
Uniprot Name
Tumor necrosis factor
Molecular Weight
25644.15 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Mimura T: [Selection of one of the TNF blockers; infliximab and etanercept]. Nihon Rinsho. 2007 Jul;65(7):1282-6. [PubMed:17642244]
  3. Braun J, Baraliakos X, Listing J, Sieper J: Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum. 2005 Aug;52(8):2447-51. [PubMed:16052578]
  4. Danese S, Sans M, Scaldaferri F, Sgambato A, Rutella S, Cittadini A, Pique JM, Panes J, Katz JA, Gasbarrini A, Fiocchi C: TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. J Immunol. 2006 Feb 15;176(4):2617-24. [PubMed:16456024]
  5. Magro F, Pereira P, Carneiro F, Veloso FT: Reactive hepatitis in a patient with Crohn's disease successfully treated with infliximab: does tumor necrosis factor alpha play a role in reactive hepatitis? Inflamm Bowel Dis. 2005 Jan;11(1):88-90. [PubMed:15674127]
  6. Mori S, Imamura F, Kiyofuji C, Ito K, Koga Y, Honda I, Sugimoto M: Pneumocystis jiroveci pneumonia in a patient with rheumatoid arthritis as a complication of treatment with infliximab, anti-tumor necrosis factor alpha neutralizing antibody. Mod Rheumatol. 2006;16(1):58-62. [PubMed:16622728]
  7. Maini RN, Feldmann M: How does infliximab work in rheumatoid arthritis? Arthritis Res. 2002;4 Suppl 2:S22-8. Epub 2002 Mar 27. [PubMed:12110154]
  8. Sapienza MS, Cohen S, Dimarino AJ: Treatment of pyoderma gangrenosum with infliximab in Crohn's disease. Dig Dis Sci. 2004 Sep;49(9):1454-7. [PubMed:15481318]
  9. Tobin AM, Kirby B: TNF alpha inhibitors in the treatment of psoriasis and psoriatic arthritis. BioDrugs. 2005;19(1):47-57. [PubMed:15691217]
  10. Shen C, Assche GV, Colpaert S, Maerten P, Geboes K, Rutgeerts P, Ceuppens JL: Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther. 2005 Feb 1;21(3):251-8. [PubMed:15691299]
  11. Popa C, Netea MG, Barrera P, Radstake TR, van Riel PL, Kullberg BJ, Van der Meer JW: Cytokine production of stimulated whole blood cultures in rheumatoid arthritis patients receiving short-term infliximab therapy. Cytokine. 2005 Apr 21;30(2):72-7. [PubMed:15804598]

Drug created on June 13, 2005 07:24 / Updated on September 17, 2020 23:29

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