Identification

Summary

Anakinra is a recombinant form of human interleukin-1 receptor antagonist used in the treatment of rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and deficiency of interleukin-1 receptor antagonist (DIRA).

Brand Names
Kineret
Generic Name
Anakinra
DrugBank Accession Number
DB00026
Background

Anakinra is a recombinant human interleukin-1 (IL-1) receptor antagonist (IL-1Ra) composed of 153 amino acid residues. Unlike native human IL-1Ra, anakinra has an additional methionine residue at the amino terminus. This drug binds to the IL-1 receptor, competing with and inhibiting the activity of IL-1 alpha and beta.7 Anakinra is indicated for the management of rheumatoid arthritis (RA) in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs), as well as the treatment of neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of interleukin-1 receptor antagonist (DIRA).7 Since IL-1 has an important role in inflammation and immunological responses, anakinra is also used for the off-label treatment of inflammatory diseases.5

A few studies have evaluated the use of anakinra for the treatment of COVID-19; however, further research is needed to validate the use of this drug in patients with COVID-19.6 Anakinra is produced using the E. Coli bacterial expression system. On November 14, 2001, it was approved by the FDA for the treatment of rheumatoid arthritis. It was later approved for the treatment of NOMID and DIRA on December 21, 2012, and December 18, 2020, respectively.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Interleukin-based products
Protein Structure
Protein Chemical Formula
C759H1186N208O232S10
Protein Average Weight
17257.6 Da
Sequences
>DB00026 sequence
MRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLG
IHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGW
FLCTAMEADQPVSLTNMPDEGVMVTKFYFQEDE
Download FASTA Format
Synonyms
  • Anakinra
  • IL-1RA
  • Interleukin-1 receptor antagonist anakinra

Pharmacology

Indication

Anakinra is an interleukin-1 receptor antagonist indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Anakinra can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents.7

Anakinra is also indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) and the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA).7 Anakinra is also used off-label for the treatment of several inflammatory diseases.5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) that blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting its ability to bind to the IL-1 type I receptor (IL-1RI). IL-1 production is higher in inflammatory diseases such as rheumatoid arthritis, where the amount of naturally occurring IL-1Ra cannot compete with the high level of IL-1 present.7

Anakinra has been associated with a higher probability of developing a severe infection, and the use of TNF blocking agents can increase this incidence.7 Hypersensitivity reactions have been reported in patients using anakinra. The prevalence of allergic reactions may be higher in patients with deficiency of interleukin-1 receptor antagonist (DIRA), since they lack the naturally occurring IL-1Ra.7 Anakinra can also decrease neutrophil counts in patients. Therefore, neutrophil counts should be assessed before initiating anakinra.7

Mechanism of action

Interleukin-1 (IL-1) plays an important role in inflammation and immunological responses. Inflammatory stimuli trigger its production, and it binds to the IL-1 receptor to activate a wide variety of mechanisms. The activity of the IL-1 receptor is also regulated by a naturally occurring IL-1 receptor antagonist (IL-1Ra) that competes for the binding sites of the IL-1 receptor.7 In rheumatoid arthritis (RA) patients, IL-1 levels are elevated, inducing cartilage degradation and the stimulation of bone resorption, and the amount of IL-1Ra in the synovium and synovial fluid of RA patients cannot compete with the high level of IL-1 present.7 Anakinra is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients.3,7

Anakinra can also be used in the treatment of neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of interleukin-1 receptor antagonist (DIRA).7 Patients with NOMID have spontaneous mutations in CIAS1/NLRP3, a gene that encodes cryopyrin, an inflammasome component. When activated, the inflammasome enhances and promotes the production of IL-1β, an isoform of IL-1.4,7 DIRA is an autoinflammatory disease caused by mutations in the IL1RN gene. These mutations reduce the amount of IL-1Ra that is secreted, leading to the unopposed action of IL-1.7 Anakinra controls NOMID and DIRA symptoms by inhibiting IL-1 activity.7

TargetActionsOrganism
AInterleukin-1 receptor type 1
antagonist
Humans
Absorption

The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3 to 7 hours later. No unexpected accumulation was observed in RA patients receiving this drug for up to 24 weeks.7 In a phase 1, single-center, randomized, sequential single-dose escalation PK study done in patients with stable RA, AUC increased in a relatively dose-proportional manner. While the tmax and Cmax fluctuated across the different doses provided to these patients (range from 0.5 to 6 mg/kg), clearance appeared to be consistent.8 In patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with a subcutaneous dose of 3 mg/kg of anakinra for an average of 3.5 years (n=16), Cmax was 3628 ng/mL and C24h was 203 ng/mL.7

Volume of distribution

In adult subjects with rheumatoid arthritis (RA) treated with anakinra (n=35), the volume of distribution averaged 18.5 L.8

Protein binding

Not Available

Metabolism

As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body.

Route of elimination

Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function.7

Half-life

In patients with rheumatoid arthritis (RA), the terminal half-life of anakinra ranged from 4 to 6 hours. In patients with neonatal-onset multisystem inflammatory disease (NOMID), the median half-life of anakinra was 5.7 h (range=3.1-28.2, n=12).7

Clearance

In patients with rheumatoid arthritis (RA), the clearance of anakinra was relatively consistent for different dose levels.8 Clearance is variable and increases with increasing creatinine clearance and body weight. However, gender and age were not significant factors.7 In patients with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the mean plasma clearance of anakinra was 16% and 50% lower, respectively. In patients with severe renal insufficiency () and end-stage renal disease (creatinine clearance < 30 mL/min), the mean plasma clearance of anakinra was 70% and 75% lower, respectively.7

Adverse Effects
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Toxicity

In clinical trials done in patients with rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra, no cases of overdose were reported.7 Sepsis trials were performed using mean calculated doses up to 35 times the ones given to patients with RA over 72 hours. Anakinra did not produce any serious toxicities at this dose range.7

In preclinical studies done in rats, where up to 100 mg/kg/day were administered either intravenously or subcutaneously over 14 days, and given at doses of 2, 20 or 200 mg/kg/day subcutaneously for 6 months, anakinra was well tolerated. Toxicity ranged from mild to moderate, and dose-related inflammation, hemorrhage and fibrosis at the injection site were detected in both rats and monkeys.9 The no observable adverse effect level (NOAEL) in rats receiving a daily subcutaneous dose of anakinra for 6 months was 2 mg/kg/day. In rats receiving a daily intravenous injection of anakinra for 14 or 28 days, the NOAEL was 30 mg/kg/day. The NOAEL in Rhesus monkeys was 150 mg/kg/day when anakinra was administered via intravenous infusion for 7 days, 10-30 mg/kg/day when administered via intravenous bolus injection for 14 days and 5 mg/kg/day when administered subcutaneously for 14 days.9 Anakinra had no effects on fertility and reproductive capacity in both male and female rats given the maximum recommended human dose.7

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.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Anakinra is combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Anakinra.
AbrocitinibThe metabolism of Abrocitinib can be increased when combined with Anakinra.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Anakinra.
AcebutololThe metabolism of Acebutolol can be increased when combined with Anakinra.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Anakinra.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Anakinra.
AcetohexamideThe metabolism of Acetohexamide can be increased when combined with Anakinra.
Acetylsalicylic acidThe metabolism of Acetylsalicylic acid can be increased when combined with Anakinra.
AcyclovirThe metabolism of Acyclovir can be increased when combined with Anakinra.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KineretInjection, solution100 mgSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-09-08Not applicableEU flag
KineretInjection, solution100 mg/0.67mLSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2009-12-15Not applicableUS flag
KineretInjection, solution100 mg/0.67mlSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-09-08Not applicableEU flag
KineretInjection, solution100 mgSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-09-08Not applicableEU flag
KineretInjection, solution100 mg/0.67mlSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-09-08Not applicableEU flag
KineretInjection, solution100 mgSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-09-08Not applicableEU flag
KineretSolution150 mg / mLSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2002-05-29Not applicableCanada flag
KineretInjection, solution100 mg/0.67mlSubcutaneousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-09-08Not applicableEU flag

Categories

ATC Codes
L04AC03 — Anakinra
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
9013DUQ28K
CAS number
143090-92-0

References

Synthesis Reference

Thompson, RC., et al. (2005). Nucleic acids encoding interleukin-1 inhibitors and processes for preparing interleukin-1 inhibitors (U.S. Patent No. US 6,858,409 B1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/cf/f9/7c/87bba89b312e38/US6858409.pdf

General References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Lequerre T, Quartier P, Rosellini D, Alaoui F, De Bandt M, Mejjad O, Kone-Paut I, Michel M, Dernis E, Khellaf M, Limal N, Job-Deslandre C, Fautrel B, Le Loet X, Sibilia J: Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis. 2008 Mar;67(3):302-8. Epub 2007 Oct 18. [Article]
  3. Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, Poulakos J, Sun G: Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum. 2003 Apr;48(4):927-34. doi: 10.1002/art.10870. [Article]
  4. Bachove I, Chang C: Anakinra and related drugs targeting interleukin-1 in the treatment of cryopyrin-associated periodic syndromes. Open Access Rheumatol. 2014 Mar 3;6:15-25. doi: 10.2147/OARRR.S46017. eCollection 2014. [Article]
  5. Cavalli G, Dinarello CA: Anakinra Therapy for Non-cancer Inflammatory Diseases. Front Pharmacol. 2018 Nov 6;9:1157. doi: 10.3389/fphar.2018.01157. eCollection 2018. [Article]
  6. Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, Kronbichler A, Shin JI: Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021 Jan 1;11(1):316-329. doi: 10.7150/thno.49713. eCollection 2021. [Article]
  7. FDA Approved Drug Products: KINERET (anakinra) subcutaneous injection [Link]
  8. FDA Clinical Pharmacology and Biopharmaceutics Review: Kineret (anakinra) subcutaneous injection [Link]
  9. FDA Clinical Pharmacology Review: Kineret (anakinra) subcutaneous injection [Link]
UniProt
P18510
Genbank
M55646
KEGG Drug
D02934
PubChem Substance
46507944
RxNav
72435
ChEMBL
CHEMBL1201570
Therapeutic Targets Database
DAP000095
PharmGKB
PA10799
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Anakinra
FDA label
Download (62.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentIdiopathic Recurrent Pericarditis1
4CompletedTreatmentRheumatoid Arthritis2
4TerminatedTreatmentRheumatoid Arthritis / Type 2 Diabetes Mellitus1
4WithdrawnTreatmentInjuries:Knee Injuries1
3Active Not RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)1
3Active Not RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Cytokine Storm1
3CompletedNot AvailableHypersecretion; Cortisol / Syndrome, Metabolic1
3CompletedTreatmentAcute Myocardial Infarction With ST Segment Elevation1
3CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1
3CompletedTreatmentFamilial Mediterranean Fever (FMF )1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amgen Inc.
  • BioVitrum AB
Dosage Forms
FormRouteStrength
Injection, solutionParenteral; Subcutaneous100 MG/0.67ML
Injection, solutionSubcutaneous100 mg/0.67mL
Injection, solutionSubcutaneous100 mg
SolutionSubcutaneous150 mg / mL
Prices
Unit descriptionCostUnit
Kineret 1 Box = 7 Syringes, 4.69ml Box449.9USD box
Kineret 100 mg/0.67 ml syr61.8USD syringe
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2141953No2008-04-082013-09-17Canada flag
CA1341322No2001-11-272018-11-27Canada flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.412Not Available
isoelectric point5.46Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Transmembrane signaling receptor activity
Specific Function
Receptor for IL1A, IL1B and IL1RN. After binding to interleukin-1 associates with the corecptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependen...
Gene Name
IL1R1
Uniprot ID
P14778
Uniprot Name
Interleukin-1 receptor type 1
Molecular Weight
65401.91 Da
References
  1. Tang YH, Zhang SP, Liang Y, Deng CQ: [Effects of Panax notoginseng saponins on mRNA expressions of interleukin-1 beta, its correlative factors and cysteinyl-aspartate specific protease after cerebral ischemia-reperfusion in rats]. Zhong Xi Yi Jie He Xue Bao. 2007 May;5(3):328-32. [Article]
  2. Dayer JM: The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis. Rheumatology (Oxford). 2003 May;42 Suppl 2:ii3-10. [Article]
  3. Vamvakopoulos J, Green C, Metcalfe S: Genetic control of IL-1beta bioactivity through differential regulation of the IL-1 receptor antagonist. Eur J Immunol. 2002 Oct;32(10):2988-96. [Article]
  4. Do H, Vasilescu A, Carpentier W, Meyer L, Diop G, Hirtzig T, Coulonges C, Labib T, Spadoni JL, Therwath A, Lathrop M, Matsuda F, Zagury JF: Exhaustive genotyping of the interleukin-1 family genes and associations with AIDS progression in a French cohort. J Infect Dis. 2006 Dec 1;194(11):1492-504. Epub 2006 Oct 26. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  6. So A, De Smedt T, Revaz S, Tschopp J: A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28. [Article]
  7. Vannier E, Kaser A, Atkins MB, Fantuzzi G, Dinarello CA, Mier JW, Tilg H: Elevated circulating levels of soluble interleukin-1 receptor type II during interleukin-2 immunotherapy. Eur Cytokine Netw. 1999 Mar;10(1):37-42. [Article]
  8. FDA Approved Drug Products: KINERET (anakinra) subcutaneous injection [Link]

Drug created at June 13, 2005 13:24 / Updated at June 03, 2022 07:24