NAV

Dupilumab

Identification

Summary

Dupilumabis a monoclonal antibody used to treat moderate to severe atopic dermatitis, asthma, and nasal polyps accompanied by chronic rhinosinusitis in adolescents and adults.

Brand Names
Dupixent
Generic Name
Dupilumab
DrugBank Accession Number
DB12159
Background

Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass that binds to the interleukin-4 (IL-4) receptor, inhibiting the receptor signaling pathways.3As an interleukin-4 receptor alpha antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, called interleukins (IL), that induce inflammatory and immunological reactions in several atopic or allergic conditions, such as eczema, allergic reaction, and rhinosinusitis.3Dupilumab was generated by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture.7

Dupilumab is commonly marketed as Dupixent, which is available as a formulation for subcutaneous injection. It was first approved by the FDA in 2017. It is currently used to treat atopic dermatitis, asthma as an add-on maintenance treatment, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis.14It is used as monotherapy or in combination with other drugs, such as corticosteroids.7,8,13Dupilumab is currently under investigations for potential therapeutic use in diseases driven by allergic reactions or type 2 inflammation, such as pediatric atopic dermatitis, and chronic obstructive pulmonary disease. It is also being studied in combination with another antibody that which targets IL-33.9

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6512H10066N1730O2052S46
蛋白质平均体重
146896.9522 Da
Sequences
>Dupilumab Heavy Chain EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
>Dupilumab Light Chain DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG DRUG: Dupilumab [Link]
Download FASTA Format
Synonyms
  • Dupilumab
External IDs
  • REGN 668
  • REGN-668
  • REGN668
  • SAR 231893
  • SAR-231893
  • SAR231893

Pharmacology

Indication

In the US, dupilumab is indicated for the treatment of patients aged six months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.15In Europe and Canada, the drug for this indication is approved for patients aged six years and older.8,13在欧洲,病人6到11岁have severe atopic dermatitis and be candidates for systemic therapy.8Dupilumab can be used with or without topical corticosteroids for this condition.7,13

Dupilumab is indicated as an add-on maintenance treatment of patients aged six years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma. However, the drug is not indicated for relief of acute bronchospasm or status asthmaticus.7,8,13

Dupilumab is indicated as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis.7In Canada and Europe, it is used with intranasal corticosteroids.8,13

In the US, dupilumab is also indicated for the treatment of adults and children aged 12 years and older weighing at least 40 kg with eosinophilic esophagitis (EoE),14and adults with prurigo nodularis.16

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Dupilumab is an recombinant human IgG4 antibody to the IL-4 receptor that works by inhibiting the activation of certain pro-inflammatory cytokines that are implicated in the pathophysiology of several allergic and atopic conditions, including asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies.In vivo, dupilumab was shown to reduce the levels of type 2 inflammatory biomarkers associated with atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH). A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed.8,9Since dupilumab works to suppress the immune response, it is proposed that it may influence the immune response against some infections, such as helminth infections, by inhibiting IL-4/IL-13 signaling. It is advised that infections are appropriately treated until resolved before initiating dupilumab therapy.8

While findings of some在vitroand在vivostudies suggest that some cytokine modulators may influence the expression and activity of specific cytochrome P450 (CYP450) enzymes, an open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied (CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6).5

Mechanism of action

Type 2 inflammatory processes in various allergic and atopic conditions, such as asthma and atopic diseases, involve the type 2 helper T-cell (Th2) immunity.4Upregulation of this Type 2/Th2 pathway is commonly observed in other inflammatory conditions5and the activation of Th2 cells is linked to the production of Th2-associated cytokines, such as interleukin (IL) 4, IL-5, IL-9, and IL-13.4IL-4 and IL-13 play a central role in inducing inflammatory conditions such as allergic rhinitis, asthma, and atopic dermatitis,9by regulating Type 2 inflammation and immune function. These inflammatory cytokines work by modulating gene expression downstream of receptor signalling,5regulating Th2 cell differentiation, and activating inflammatory cells such as mast cells and macrophages.6

There are two types of receptors for IL-4: the type 1 receptor, which is composed of the IL-4 chain (IL-4Rα) and a γ chain (γC), and the type 2 receptor, which is composed of the IL-4Rα chain and the α1 chain of the IL-13 receptor (IL-13Rα1).4Essentially, IL‐4Rα is a component shared by the IL‐4 and IL-13 receptor complexes3and is ubiquitously expressed on both innate and adaptive immune cells to promote the signaling of IL-4 and IL-13.6The type I receptor is primarily expressed on lymphocytes and controls Th2-cell differentiation, whereas the type II receptor is mostly found across resident and myeloid cells.1Dupilumab is a fully human monoclonal antibody directed against IL‐4Rα to inhibit the signalling of IL‐4 and IL‐13.5Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα).8It ultimately downregulates type-2 immunity.4

Target Actions Organism
AInterleukin-4 receptor subunit alpha
在hibitor
antibody
 Humans
AInterleukin-13
在hibitor
antibody
 Humans
AInterleukin-4
在hibitor
antibody
 Humans
Absorption

The Cmax following administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab were 70.1 ± 24.1 mcg/mL or 41.8 ± 12.4 mcg/mL, respectively. The Tmax ranged from 3 to 7 days following administration of a single subcutaneous dose ranging from 75 to 600 mg.7Following a subcutaneous dose, the absolute bioavailability of dupilumab ranged between 61% and 64% in patients with atopic dermatitis or asthma.8

In clinical trials, the steady-state concentrations were reached by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. At these concentrations, the mean trough concentrations ranged from 60.3 ± 35.1 mcg/mL to 79.9 ± 41.4 mcg/mL for 300 mg dose and from 29.2 ± 18.7 to 36.5 ± 22.2 mcg/mL for 200 mg dose administered every other week.7

Volume of distribution

The estimated volume of distribution is 4.8 ± 1.3 L.3

Protein binding

There is limited data on the serum protein binding profile of dupilumab.

Metabolism

Being a monoclonal antibody, dupilumab is not expected to undergo significant hepatic metabolism.8While the metabolism of dupilumab has not been characterized, it is speculated that dupilumab undergoes nonspecific degradation into smaller peptides and amino acids, as often observed with endogenous IgG.3

Route of elimination

Being a monoclonal antibody, dupilumab is not expected to undergo significant renal elimination. It is proposed that dupilumab is eliminated via parallel linear and nonlinear pathways. At higher concentrations, dupilumab is primarily cleared through a non-saturable proteolytic pathway. At lower concentrations, it undergoes a non-linear saturable IL-4R α target-mediated elimination.8

Half-life

There is limited human data on the half-life of dupilumab.8In single-dose pharmacokinetic studies, the mean half-life of dupilumab following intravenous or subcutaneous administration ranged from 4.8 to 7 days in rats and 11.7 to 20.5 days in cynomolgus monkeys.11,12In these studies, the mean half-life was comparable was comparable following intravenous and subcutaneous administration.11

Clearance

There is limited data on the clearance of dupilumab.8

Adverse Effects
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Toxicity

There is limited data on the overdose of dupilumab. As there is no specific treatment for dupilumab, close monitoring of the patient with appropriate symptomatic treatment is advised in case of suspected overdosage.[]

Pathways
Not Available
Pharmacogenomic Effects/ADRsBrowse all" title="" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug InteractionsLearn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
Integrate drug-drug
在teractions in your software
Abciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Dupilumab.
Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Dupilumab.
Adenovirus type 7 vaccine live 腺病毒7 vacc型的治疗效果在e live can be decreased when used in combination with Dupilumab.
Aducanumab The risk or severity of adverse effects can be increased when Dupilumab is combined with Aducanumab.
Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Dupilumab.
Alirocumab The risk or severity of adverse effects can be increased when Alirocumab is combined with Dupilumab.
Amivantamab The risk or severity of adverse effects can be increased when Dupilumab is combined with Amivantamab.
Anifrolumab The risk or severity of adverse effects can be increased when Anifrolumab is combined with Dupilumab.
Ansuvimab The risk or severity of adverse effects can be increased when Dupilumab is combined with Ansuvimab.
Anthrax immune globulin human The risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Dupilumab.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image
Dupixent Injection, solution 150 mg/ml Subcutaneous Sanofi Aventis Groupe 2020-12-16 Not applicable EU flag
Dupixent Injection, solution 175 mg/ml Subcutaneous Sanofi Aventis Groupe 2020-12-16 Not applicable EU flag
Dupixent Injection, solution 150 mg/ml Subcutaneous Sanofi Aventis Groupe 2020-12-16 Not applicable EU flag
Dupixent Injection, solution 300 mg/2mL Subcutaneous sanofi-aventis U.S. LLC 2017-03-28 2017-03-28 US flag
Dupixent Solution 200 mg / 1.14 mL Subcutaneous Sanofi Aventis 2022-06-23 Not applicable Canada flag
Dupixent Solution 150 mg / mL Subcutaneous Sanofi Aventis 2018-02-06 Not applicable Canada flag
Dupixent Injection, solution 175 mg/ml Subcutaneous Sanofi Aventis Groupe 2020-12-16 Not applicable EU flag
Dupixent Injection, solution 150 mg/ml Subcutaneous Sanofi Aventis Groupe 2020-12-16 Not applicable EU flag
Dupixent Injection, solution 150 mg/ml Subcutaneous Sanofi Aventis Groupe 2020-12-16 Not applicable EU flag
Dupixent Injection, solution 300 mg/2mL Subcutaneous sanofi-aventis U.S. LLC 2020-06-19 Not applicable US flag

Categories

ATC Codes
D11AH05 — Dupilumab
Drug Categories
Chemical TaxonomyProvided byClassyfire
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
420K487FSG
CAS number
1190264-60-8

References

通用再保险公司ferences
  1. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G: Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. doi: 10.1056/NEJMoa1304048. Epub 2013 May 21. [Article]
  2. Frampton JE, Blair HA: Dupilumab: A Review in Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol. 2018 Aug;19(4):617-624. doi: 10.1007/s40257-018-0370-9. [Article]
  3. D'Ippolito D, Pisano M: Dupilumab (Dupixent): An Interleukin-4 Receptor Antagonist for Atopic Dermatitis. P T. 2018 Sep;43(9):532-535. [Article]
  4. Sastre J, Davila I: Dupilumab: A New Paradigm for the Treatment of Allergic Diseases. J Investig Allergol Clin Immunol. 2018 Jun;28(3):139-150. doi: 10.18176/jiaci.0254. [Article]
  5. Davis JD, Bansal A, Hassman D, Akinlade B, Li M, Li Z, Swanson B, Hamilton JD, DiCioccio AT: Evaluation of Potential Disease-Mediated Drug-Drug Interaction in Patients With Moderate-to-Severe Atopic Dermatitis Receiving Dupilumab. Clin Pharmacol Ther. 2018 Dec;104(6):1146-1154. doi: 10.1002/cpt.1058. Epub 2018 Apr 2. [Article]
  6. Hurdayal R, Brombacher F: Interleukin-4 Receptor Alpha: From Innate to Adaptive Immunity in Murine Models of Cutaneous Leishmaniasis. Front Immunol. 2017 Nov 10;8:1354. doi: 10.3389/fimmu.2017.01354. eCollection 2017. [Article]
  7. FDA Approved Drug Products: Dupixent (dupilumab) for subcutaneous injection [Link]
  8. EMA Approved Drug Products: Dupixent (dupilumab) subcutaneous injection [Link]
  9. Dupixent® (dupilumab) Approved for Severe Asthma by European Commission - Regeneron [Link]
  10. FDA approves first treatment for chronic rhinosinusitis with nasal polyps [Link]
  11. European Medicines Agency: Dupixent (dupilumab) Public Assessment Report [Link]
  12. Australian Public Assessment Report for Dupilumab - TGA [Link]
  13. Health Canada Approved Drug Products: DUPIXENT (dupilumab) subcutaneous injection [Link]
  14. FDA Approved Drug Products: Dupixent (dupilumab) for subcutaneous injection (May 2022) [Link]
  15. FDA Approved Drug Products: DUPIXENT (dupilumab) injection, for subcutaneous use (June 2022) [Link]
  16. FDA Approved Drug Products: DUPIXENT (dupilumab) injection, for subcutaneous use (September 2022) [Link]
PubChem Substance
347911292
RxNav
1876376
Wikipedia
Dupilumab

Clinical Trials

Clinical TrialsLearn More" title="" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count
4 Active Not Recruiting Treatment Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP) 1
4 Completed Basic Science Atopic Dermatitis 1
4 Completed Treatment Atopic Dermatitis 4
4 Not Yet Recruiting Treatment Atopic Dermatitis 5
4 Not Yet Recruiting Treatment Atopic Dermatitis/Moderate to Severe Atopic Dermatitis 1
4 Recruiting Basic Science Asthma 1
4 Recruiting Basic Science Atopic Dermatitis 1
4 Recruiting Treatment Allergic Contact Dermatitis 1
4 Recruiting Treatment Aspirin Exacerbated Respiratory Disease (AERD) 1
4 Recruiting Treatment Asthma 7

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Form Route Strength
Injection Subcutaneous
Injection, solution Parenteral; Subcutaneous 200 MG
Injection, solution Parenteral; Subcutaneous 300 MG
Injection, solution Subcutaneous 100 mg/0.67mL
Injection, solution Subcutaneous 150 mg/ml
Injection, solution Subcutaneous 175 mg/ml
Injection, solution Subcutaneous 200 mg/1.14mL
Injection, solution Subcutaneous 300 mg/2mL
Solution Subcutaneous 100 mg / 0.67 mL
Solution Subcutaneous 150 mg / mL
Solution Subcutaneous 200 mg / 1.14 mL
Injection, solution 150 mg/ml
Solution Subcutaneous 200 mg
Injection, solution Subcutaneous
Solution Subcutaneous 300 mg
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Details 1.Interleukin-4 receptor subunit alpha
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Antibody
General Function
Receptor signaling protein activity
Specific Function
Receptor for both interleukin 4 and interleukin 13. Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regu...
Gene Name
IL4R
Uniprot ID
P24394
Uniprot Name
Interleukin-4 receptor subunit alpha
分子量
89657.42 Da
References
  1. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G: Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. doi: 10.1056/NEJMoa1304048. Epub 2013 May 21. [Article]
Details 2.Interleukin-13
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Antibody
General Function
Interleukin-13 receptor binding
Specific Function
Cytokine. Inhibits inflammatory cytokine production. Synergizes with IL2 in regulating interferon-gamma synthesis. May be critical in regulating inflammatory and immune responses.
Gene Name
IL13
Uniprot ID
P35225
Uniprot Name
Interleukin-13
分子量
15815.585 Da
References
  1. Agarwal A, Spath D, Sherris DA, Kita H, Ponikau JU: Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed? Clin Rev Allergy Immunol. 2020 Oct;59(2):141-149. doi: 10.1007/s12016-019-08734-z. [Article]
Details 3.Interleukin-4
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Antibody
General Function
Interleukin-4 receptor binding
Specific Function
Participates in at least several B-cell activation processes as well as of other cell types. It is a costimulator of DNA-synthesis. It induces the expression of class II MHC molecules on resting B-...
Gene Name
IL4
Uniprot ID
P05112
Uniprot Name
Interleukin-4
分子量
17492.09 Da
References
  1. Agarwal A, Spath D, Sherris DA, Kita H, Ponikau JU: Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed? Clin Rev Allergy Immunol. 2020 Oct;59(2):141-149. doi: 10.1007/s12016-019-08734-z. [Article]

Drug created at October 20, 2016 21:30 / Updated at December 01, 2022 11:27