Rituximab

Identification

Name
Rituximab
Accession Number
DB00073
Description

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light and heavy-chain variable region sequences and human constant region sequences 6, Label. It was originally approved by the U.S. FDA in 1997 as a single agent to treat patients with B-cell Non-Hodgkin's Lymphoma (NHL) 8, however, has now been approved for a variety of conditions Label. On November 28, 2018, the US FDA approved Truxima, the first biosimilar to Rituxan (Rituximab) 7.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db00073
Protein Chemical Formula
C6416H9874N1688O1987S44
Protein Average Weight
143859.7 Da
Sequences
>Rituximab heavy chain chimeric
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSY
NQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVS
AASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Rituximab light chain chimeric
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVR
FSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Rituximab - CAS 174722-31-7 [Link]
Download FASTA Format
Synonyms
  • rituximab-abbs
  • rituximab-pvvr
External IDs
  • GP2013
  • IDEC-102
  • IDEC-C2B8
  • PF 05280586
  • PF-05280586
  • RG-105

Pharmacology

Indication

Rituximab is indicated in the following conditions Label:

Non–Hodgkin’s Lymphoma (NHL)

Chronic Lymphocytic Leukemia (CLL)

Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

Moderate to severe Pemphigus Vulgaris (PV) in adult patients

The biosimilar (approved in November 2018), Truxima, is indicated For the treatment of adult patients with CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL) to be used as a single agent or in combination with chemotherapy 7.

In September 2019, the rituximab injection was approved along with glucocorticoids to manage granulomatosis with polyangiitis (GPA) in addition to microscopic polyangiitis (MPA) in children of at least 2 years of age 9.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Rituximab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lymphomas 1. The antibody leads to selective killing of B-cells. The following are the pharmacodynamic outcomes for various conditions, including non- Hodgkin's Lymphoma Label:

Non-Hodgkin’s Lymphoma (NHL) In Non-Hodgkin's Lymphoma patients, the administration of rituximab led to the depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks, showing sustained depletion for up to 6-9 months post-treatment in 83% of treated patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following the completion of treatment Label. There were sustained and statistically significant decreases in serum IgM and IgG levels measured from 5-11 months following rituximab administration; 14% of patients showed IgM and/or IgG serum levels below the normal range Label.

Rheumatoid Arthritis In rheumatoid arthritis (RA) patients, treatment with rituximab induced the depletion of peripheral B lymphocytes, with the majority of patients showing near complete depletion (CD19 counts below the lower limit of quantification, 20 c-lls/μl) within 2 weeks after the first dose of rituximab. The majority of treated patients showed peripheral B-cell depletion, sustained for a minimum of 6 months. A small percentage of patients (~4%) had peripheral B-cell depletion that was sustained for more than 3 years after one course of treatment. Total serum immunoglobulin levels, IgM, IgG, and IgA were decreased at 6 months with the greatest change observed in IgM. At Week 24 of the first cycle of rituximab treatment, small percentages of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). When rituximab was administered to RA patients during repeated rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with rituximab are not clear at this time. Treatment with rituximab in patients with RA was associated with a decreased level of several biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF Label and was found to decrease disease symptoms 2.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis In GPA and MPA patients, peripheral blood CD19 B-cells were depleted to less than 10 cells/μl after the first two infusions of rituximab, and remained at the same level in most (84%) patients through Month 6 of the treatment. By Month 12, most patients (81%) demonstrated signs of B-cell return with counts >10 cells/μL. By Month 18, the majority of patients (87%) had counts >10 cells/μL Label.

Mechanism of action

Rituximab is a monoclonal antibody that targets the CD20 antigen, which is expressed on the surface of pre-B and mature B-lymphocytes 1, 2, 3, Label. After binding to CD20, rituximab mediates B-cell lysis (or breakdown). The possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC) Label.

Rituximab belongs to the immunoglobulin G1 (IgG1) sub-class, consisting of a murine variable region (Fab region) and a human constant region (Fc region). The Fab region has variable sections that define a specific target antigen, allowing the antibody to attract and secure its exclusive antigen, specifically the binding of rituximab (IgG1) to CD20 on pre-B and mature B lymphocytes. The Fc region is the tail end of the antibody that communicates with cell surface receptors to activate the immune system, in this case, a sequence of events leading to the depletion of circulating B lymphocytes by complement-dependent cell lysis, antibody-dependent cellular cytotoxicity, as well as apoptosis 6.

In regards to the mechanism of action in rheumatoid arthritis, B cells are thought to play a role in the pathogenesis of rheumatoid arthritis (RA) and the associated condition of chronic synovitis. B cells may act at various sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or the production of proinflammatory cytokines Label. The administration of rituximab in this condition has been shown to result in significant clinical and symptomatic improvements 2, Label.

TargetActionsOrganism
AB-lymphocyte antigen CD20
antibody
Humans
Absorption

Following the administration of 2 doses of rituximab in patients with rheumatoid arthritis (RA), the mean (± S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were : 157 ( ± 46; 29%) and 183 ( ± 55; 30%) mcg/mL, and 318 ( ± 86; 27%) and 381 ( ± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1000 mg doses, respectively Label.

Volume of distribution

3.1 L in Rheumatoid Arthritis Label

4.5 L in Granulomatosis with polyangitis and microscopic polyangitis Label

Protein binding
Not Available
Metabolism

Most likely removed by opsonization via the reticuloendothelial system 5.

Route of elimination

Likely eliminated through the reticuloendothelial system 5.

Half-life

Non-Hodgkin's Lymphoma: Based on a population pharmacokinetic analysis of data from 298 Non-Hodgkin's Lymphoma (NHL) patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days) Label.

Rheumatoid Arthritis: Mean terminal elimination half-life was 18.0 days in patients with rheumatoid arthritis Label Based on a population pharmacokinetic analysis of data from 2005 RA patients who received rituximab Label.

Chronic Lymphocytic Leukemia (CLL): Pharmacokinetics were studied in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14-62 days) Label.

Granulomatosis with Polyangitis and Microscopic Polyangitis: Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m2 rituximab once weekly by intravenous infusion for four weeks, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days) Label.

Clearance

Rheumatoid Arthritis: 0.335 L/day Label

Granulomatosis with Polyangitis and Microscopic Polyangitis: 0. 312 L/day Label

Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance Label.

Adverse Effects
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Toxicity

Oral LD50: 27 mg/kg (mouse and rat) MSDS

Inhalation LD50: 32 mg/m3 (mouse) and 37 mg/m3 (rat) MSDS

Skin LD50: 20 mg/kg (rabbit) and 50 mg/kg (rat) MSDS

Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab or to determine potential effects on fertility in males or females Label.

Embryo-Fetal toxicity: Can cause neonatal harm. Advise of potential risk to neonates and use of effective contraception 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-AFCGR3A(G;G) / (G;T)T > GEffect Directly StudiedPatients with this genotype have increased frequency of anti-tumor response when using rituximab to treat diffuse large B-cell lymphoma, follicular lymphoma, or [follicular non-Hodgkin lymphoma].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
AbataceptRituximab may increase the immunosuppressive activities of Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Rituximab.
AcebutololAcebutolol may increase the hypotensive activities of Rituximab.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Rituximab.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Rituximab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Rituximab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Rituximab.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Rituximab.
AlefaceptThe risk or severity of adverse effects can be increased when Rituximab is combined with Alefacept.
AlemtuzumabThe risk or severity of adverse effects can be increased when Rituximab is combined with Alemtuzumab.
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
MabThera (Roche)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RituxanInjection, solution10 mg/1mLIntravenousGenentech, Inc.1997-11-26Not applicableUS flag
RituxanInjection, solution10 mg/1mLIntravenousGenentech, Inc.1997-11-26Not applicableUS flag
RituxanSolutionIntravenousHoffmann La Roche2000-03-20Not applicableCanada flag
Rituxan ScSolutionSubcutaneousHoffmann La Roche2018-04-24Not applicableCanada flag
Rituxan ScSolutionSubcutaneousHoffmann La Roche2016-11-22Not applicableCanada flag
RiximyoSolutionIntravenousSandoz Canada Incorporated2020-05-22Not applicableCanada flag
RuxienceSolution10 mgIntravenousPfizer Canada Ulc2020-05-26Not applicableCanada flag
RuxienceInjection, solution500 mg/50mLIntravenousPfizer Laboratories Div Pfizer Inc2020-01-23Not applicableUS flag
RuxienceInjection, solution100 mg/10mLIntravenousPfizer Laboratories Div Pfizer Inc2020-01-23Not applicableUS flag
TruximaSolution100 mgIntravenousCelltrion2019-12-11Not applicableCanada 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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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Rituxan HycelaRituximab (120 mg/1mL) + Hyaluronidase (human recombinant) (2000 U/1mL)Injection, solutionSubcutaneousGenentech, Inc.2017-06-22Not applicableUS flag
Rituxan HycelaRituximab (120 mg/1mL) + Hyaluronidase (human recombinant) (2000 U/1mL)Injection, solutionSubcutaneousGenentech, Inc.2017-06-22Not applicableUS flag

Categories

ATC Codes
L01XC02 — Rituximab
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
4F4X42SYQ6
CAS number
174722-31-7

References

General References
  1. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. [PubMed:9704735]
  2. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81. [PubMed:15201414]
  3. Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, Andersen I, Schmidt K, Andersen TM, Peterslund NA, Birgens HS, Plesner T, Pedersen BB, Hasselbalch HC: Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol. 2005 Apr;78(4):275-80. [PubMed:15795920]
  4. Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M: The epitope recognized by rituximab. Blood. 2006 Sep 15;108(6):1975-8. Epub 2006 May 16. [PubMed:16705086]
  5. Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [PubMed:28653357]
  6. Emer JJ, Claire W: Rituximab: a review of dermatological applications. J Clin Aesthet Dermatol. 2009 May;2(5):29-37. [PubMed:20729962]
  7. FDA approves first biosimilar for treatment of adult patients with non-Hodgkin’s lymphoma [Link]
  8. FDA Approves Two New Indications for Rituxan in Patients With Non-Hodgkin's Lymphoma [Link]
  9. FDA approves first treatment for children with rare diseases that cause inflammation of small blood vessels [Link]
UniProt
P01857
Genbank
J00228
PubChem Substance
46505820
RxNav
121191
ChEMBL
CHEMBL1201576
Therapeutic Targets Database
DAP000382
PharmGKB
PA451261
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Rituximab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (257 KB)
MSDS
Download (117 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAnti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Granulomatosis With Polyangiitis / Microscopic Polyangiitis1
4Active Not RecruitingTreatmentFunction of Renal Transplant1
4Active Not RecruitingTreatmentNeuromyelitis Optica Spectrum Disorder1
4CompletedOtherAutoimmune Diseases / Transplant, Kidney1
4CompletedPreventionAutoimmune Adrenocortical Failure1
4CompletedPreventionTransplantation, Kidney1
4CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
4CompletedTreatmentAdult Acute Lymphocytic Leukemia1
4CompletedTreatmentBurkitt's Lymphoma / Large Cell Anaplastic Lymphoma / Lymphoma, Lymphoblastic / Mediastinal Neoplasms1
4CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1

Pharmacoeconomics

Manufacturers
  • Roche
Packagers
  • Biogen Idec Inc.
  • F Hoffmann-La Roche Ltd.
  • Genentech Inc.
Dosage Forms
FormRouteStrength
Solution, concentrateIntravenous500 mg
Injection, solutionCutaneous1400 MG
InjectionIntravenous100 mg
Injection, solutionIntravenous120 mg/mL
InjectionIntravenous500 mg/50ml
Solution
SolutionSubcutaneous1400 mg
SolutionIntravenous100 mg/10ml
SolutionIntravenous500 mg/50ml
Injection, solutionIntravenous10 mg/1mL
Injection, solutionSubcutaneous
SolutionSubcutaneous
Injection, solution, concentrateIntravenous100 MG
Injection, solution, concentrateIntravenous500 MG
SolutionIntravenous
Injection, solutionIntravenous100 mg/10mL
Injection, solutionIntravenous500 mg/50mL
SolutionIntravenous10 mg
Injection, solution, concentrateIntravenous; Parenteral100 MG
Injection, solution, concentrateIntravenous; Parenteral500 MG
SolutionIntravenous100 mg
SolutionIntravenous500 mg
Injection, solution
Prices
Unit descriptionCostUnit
Rituxan 10 mg/ml Concentrate 10ml Vial708.17USD vial
Rituxan 10 mg/ml vial68.09USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2149329No2008-07-152013-11-12Canada flag
CA1336826No1995-08-292012-08-29Canada flag
US5736137No1998-04-072015-04-07US 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)http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1062
hydrophobicity-0.414http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1062
isoelectric point8.68http://crdd.osdd.net/raghava/thpdb/display_thppid_sub.php?details=Th1062

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Mhc class ii protein complex binding
Specific Function
This protein may be involved in the regulation of B-cell activation and proliferation.
Gene Name
MS4A1
Uniprot ID
P11836
Uniprot Name
B-lymphocyte antigen CD20
Molecular Weight
33076.99 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. van Meerten T, Hagenbeek A: CD20-targeted therapy: the next generation of antibodies. Semin Hematol. 2010 Apr;47(2):199-210. doi: 10.1053/j.seminhematol.2010.01.007. [PubMed:20350667]
  3. Jaglowski SM, Byrd JC: Rituximab in chronic lymphocytic leukemia. Semin Hematol. 2010 Apr;47(2):156-69. doi: 10.1053/j.seminhematol.2010.01.005. [PubMed:20350663]
  4. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. [PubMed:9704735]
  5. Rituxan FDA label [File]

Drug created on June 13, 2005 07:24 / Updated on September 27, 2020 08:17

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