Anakinra

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

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. A few studies have evaluated the use of anakinra for the treatment of coronavirus disease 2019 (COVID-19).⁶ On November 8, 2022, the FDA issued an emergency use authorization (EUA) of anakinra for the treatment of COVID-19 in hospitalized patients who are at risk of progressing to severe respiratory failure.¹¹

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

The FDA has issued an emergency use authorization (EUA) for the emergency use of anakinra for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults with positive results of direct SARS-CoV-2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Since anakinra is approved for this condition under EUA, the drug should only be used when there are no alternative treatment available.¹⁰

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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

Target	Actions	Organism
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 t_max and C_max 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), C_max was 3628 ng/mL and C_24h 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.

Drug	Interaction
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Abatacept	The risk or severity of adverse effects can be increased when Anakinra is combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Anakinra.
Abrocitinib	The metabolism of Abrocitinib can be increased when combined with Anakinra.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Anakinra.
Acebutolol	The metabolism of Acebutolol can be increased when combined with Anakinra.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Anakinra.
Acetaminophen	The metabolism of Acetaminophen can be increased when combined with Anakinra.
Acetohexamide	The metabolism of Acetohexamide can be increased when combined with Anakinra.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be increased when combined with Anakinra.
Acyclovir	The 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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Kineret	Injection, solution	100 mg	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2016-09-08	Not applicable
Kineret	Injection, solution	100 mg	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2016-09-08	Not applicable
Kineret	Injection, solution	100 mg/0.67ml	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2016-09-08	Not applicable
Kineret	Solution	150 mg / mL	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2002-05-29	Not applicable
Kineret	Injection, solution	100 mg	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2016-09-08	Not applicable
Kineret	Injection, solution	100 mg/0.67ml	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2016-09-08	Not applicable
Kineret	Injection, solution	100 mg/0.67mL	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2009-12-15	Not applicable
Kineret	Injection, solution	100 mg/0.67ml	Subcutaneous	SWEDISH ORPHAN BIOVITRUM AB (PUBL)	2016-09-08	Not applicable

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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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]
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]
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]
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]
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]
FDA Approved Drug Products: KINERET (anakinra) subcutaneous injection [Link]
FDA Clinical Pharmacology and Biopharmaceutics Review: Kineret (anakinra) subcutaneous injection [Link]
FDA Clinical Pharmacology Review: Kineret (anakinra) subcutaneous injection [Link]
FDA Emergency Use Authorization (EUA) Drug Products: KINERET (anakinra) injection, for subcutaneous use [Link]
FDA Letter of Authorization (LOA): Kineret LOA 11082022 [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Idiopathic Recurrent Pericarditis	1
4	Completed	Treatment	Rheumatoid Arthritis	2
4	Terminated	Treatment	Rheumatoid Arthritis / Type 2 Diabetes Mellitus	1
4	Withdrawn	Treatment	Injuries:Knee Injuries	1
3	Active Not Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / Cytokine Storm	1
3	Completed	Not Available	Hypersecretion; Cortisol / Syndrome, Metabolic	1
3	Completed	Treatment	Acute Myocardial Infarction With ST Segment Elevation	1
3	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	2
3	Completed	Treatment	Familial Mediterranean Fever (FMF )	1
3	Completed	Treatment	Hypogonadism / Obesity / Syndrome, Metabolic	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Amgen Inc.
BioVitrum AB

Dosage Forms

Form	Route	Strength
Injection, solution	Parenteral; Subcutaneous	100 MG/0.67ML
Injection, solution	Subcutaneous	100 mg
Injection, solution	Subcutaneous	100 mg/0.67mL
Solution	Subcutaneous	150 mg / mL

Prices

Unit description	Cost	Unit
Kineret 1 Box = 7 Syringes, 4.69ml Box	449.9USD	box
Kineret 100 mg/0.67 ml syr	61.8USD	syringe

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2141953	No	2008-04-08	2013-09-17
CA1341322	No	2001-11-27	2018-11-27

Properties

State

Liquid

Experimental Properties

Property	Value	Source
hydrophobicity	-0.412	Not Available
isoelectric point	5.46	Not Available

Targets

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insights and accelerate drug research.

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Details1. Interleukin-1 receptor type 1

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

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]
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]
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]
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]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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]
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]
FDA Approved Drug Products: KINERET (anakinra) subcutaneous injection [Link]

Drug created at June 13, 2005 13:24 / Updated at November 14, 2022 19:57

Anakinra

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References