Abatacept

Abatacept
Names
Trade namesOrencia
Clinical data
Drug classT cell costimulation modulator[1]
Main usesRheumatoid arthritis, juvenile idiopathic arthritis, arthritis associated with psoriasis, graft versus host disease (GVHD)[1][2]
Side effectsUpper respiratory tract infections, headache, nausea[2][1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: C
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous, subcutaneous
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa606016
    Legal
    License data
    Legal status
    Pharmacokinetics
    Elimination half-life13.1 days
    Chemical and physical data
    FormulaC3498H5458N922O1090S32
    Molar mass78895.43 g·mol−1

    Abatacept, sold under the brand name Orencia, is a medication used to treat rheumatoid arthritis, juvenile idiopathic arthritis, and arthritis associated with psoriasis.[2] It may also be used to prevent graft versus host disease (GVHD).[1] It is usually given by injection into a vein, or under the skin.[3] The dose and frequency depend on a person's body weight.[3]

    Common side effects include upper respiratory tract infections, headache, and nausea.[2][1] Other side effects include anaphylaxis and infection.[1] It is generally not given in pregnancy; birth control is recommended during treatment and for 14 weeks after.[3] It works by attaching to and blocking CD80 and CD86; thereby decreasing the immune activity of T cells.[2][4]

    Abatacept was approved for medical use in the United States in 2005 and Europe in 2007.[1][2] In the United Kingdom, a typical month of a maintenance dose costs the NHS about £1,500 as of 2021.[3] In the United States this amount costs about 2,600 to 5,200 USD.[5]

    Medical uses

    Abatacept is used to treat adults with moderate to severe rheumatoid arthritis (RA) as a second-line agent, and as a first-line agent for people whose RA is severe and rapidly progressing. It also used to treat psoriatic arthritis and juvenile idiopathic arthritis.[6][7][8]

    Dosage

    The intravenous formulation is given based on a person's weight.[3] For those less than 60 kg, three separate doses of 500 mg are given each two weeks apart. Then long term 500 mg is given every 4 weeks.[3] For those 60 to 100 kg 750 mg is used while in those more than 100 kg 1,000 mg is used.[3]

    Contraindications

    Abatacept has not been tested in pregnant women and it is not known if it is secreted in breast milk; it causes birth defects in rodents when given in very high doses, and is transmitted in rodent breast milk.[7]

    People should be tested for tuberculosis and any infection cleared before starting abatacept; vaccines should be updated prior to starting abatacept as well. Abatacept will likely interfere with any vaccine given while people are taking it.[7]

    It should not be used in combination with anakinra or TNF antagonists.[9] Because abatacept, anakinra, and TNF antagonists suppress the immune system, using them in combination may significantly increase the risk for severe infections.[6]

    Side effects

    People have experienced serious infections due to abatacept's suppression of the immune system; some of these infections have been fatal. People with COPD are likely to get lung infections more often than usual. Some people have had anaphylactic reactions. Abatacept may cause otherwise slow-growing cancers to proliferate and spread, due to suppression of the immune system.[7]

    Very common adverse effects (occurring in more than 10% of people) include upper respiratory tract infections. Common adverse effects (occurring in between 1% and 10% of people) include lower respiratory tract infections, urinary tract infections, herpes infections, pneumonia, flu, cough, high blood pressure, stomach pain, diarrhea, nausea, vomiting, upset stomach, mouth sores, elevated transaminases, rashes, fatigue, weakness, local injection site reactions, and systemic injection reactions.[7]

    Mechanism of action

    Abatacept prevents antigen-presenting cells (APCs) from delivering the co-stimulatory signal. This prevents the T cells from being fully activated, and even downregulates them. Simple signaling without co-stimulation allows the cell to recognize the primary signal as "self" and not ramp-up responses for future responses as well.

    In order for T cells to be activated and attack an antigen, that antigen must be presented to the T cell by an antigen-presenting cell (APC).

    That activation requires two signals (one of which is called co-stimulatory signal or signal 2):

    For signal 1, the APC must bind the antigen to a major histocompatibility complex (MHC) molecule, bring that complex to its surface, and present it to the T cell receptor on the surface of the T cell.

    For signal 2, the APC must present a B7 protein on its cell surface to a CD28 protein on the surface of the T cell. These two signals activate the T cell. Without signal 2, the T cell will not be activated, and will become anergic.

    Abatacept consists of a fusion protein of the extracellular domain of CTLA-4 and human IgG1, binds to the B7 protein on the APC and prevents it from delivering the co-stimulatory signal to the T cell.[10][11]

    Chemistry

    Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 with the hinge, CH2, and CH3 domains of IgG1.[9]

    History

    Abatacept was developed by Bristol-Myers Squibb and is licensed in the United States for the treatment of rheumatoid arthritis in the case of inadequate response to anti-TNFα therapy.

    Society and culture

    Cost

    In the United Kingdom, a typical monthly cost of a maintenance dose for the NHS is between £1,200-£1,800 depending on the size of the person.[3]

    In the United States this amount costs about 2,600 to 5,200 USD.[12] Some doctors in 2016 criticize its cost at the time ($3,500 to $3,800 a month, like other biological drugs of its class) and its promotional marketing.[13]

    Research

    Abatacept is the basis for the second-generation belatacept currently being tested in clinical trials. They differ by only 2 amino acids. In organ transplantation, belatacept is intended to provide extended graft survival while limiting the toxicity generated by standard immune-suppressing regimens such as calcineurin inhibitors (for example cyclosporin).

    References

    1. 1 2 3 4 5 6 7 "DailyMed - ORENCIA- abatacept injection, powder, lyophilized, for solution ORENCIA- abatacept injection, solution". dailymed.nlm.nih.gov. Archived from the original on 24 March 2021. Retrieved 12 January 2022.
    2. 1 2 3 4 5 6 7 "Orencia EPAR". European Medicines Agency (EMA). Archived from the original on 8 November 2021. Retrieved 6 October 2020.
    3. 1 2 3 4 5 6 7 8 "10. Musculoskeletal system". British National Formulary (BNF) (82 ed.). London: BMJ Group and the Pharmaceutical Press. September 2021 – March 2022. pp. 1165–1166. ISBN 978-0-85711-413-6.{{cite book}}: CS1 maint: date format (link)
    4. ↑ Shagroni, T.; Cazares, Ramirez; Kim, J. A.; Furst, Daniel E. (2020). "36. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, & drugs used in gout". In Katzung, Bertram G.; Trevor, Anthony J. (eds.). Basic and Clinical Pharmacology (15th ed.). New York: McGraw-Hill. p. 674. ISBN 978-1-260-45231-0. Archived from the original on 2021-10-10. Retrieved 2021-11-08.
    5. ↑ "Orencia Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 8 March 2016. Retrieved 9 November 2021.
    6. 1 2 "US Abatacept label" (PDF). FDA. June 2017. Archived (PDF) from the original on 2019-08-26. Retrieved 2017-08-12. For label updates, see FDA index page for BLA 125118 Archived 2019-08-26 at the Wayback Machine
    7. 1 2 3 4 5 "UK label prefilled pen". UK Electronic Medicines Compendium. 25 July 2017. Archived from the original on 9 November 2021. Retrieved 9 November 2021.
    8. ↑ "UK label powder". UK Electronic Medicines Compendium. 25 July 2017. Archived from the original on 12 August 2017. Retrieved 12 August 2017.
    9. 1 2 Moreland L, Bate G, Kirkpatrick P (2006). "Abatacept". Nature Reviews Drug Discovery. 5 (3): 185–186. doi:10.1038/nrd1989. PMID 16557658.
    10. ↑ "ABATACEPT & BELATACEPT: the CTLA-4-Igs". Healthvalue.net. Archived from the original on 2008-12-05. Retrieved 2007-05-25.
    11. ↑ Dall'Era M, Davis J (2004). "CTLA4Ig: a novel inhibitor of co-stimulation". Lupus. 13 (5): 372–376. doi:10.1191/0961203303lu1029oa. PMID 15230295. S2CID 32235606.
    12. ↑ "Orencia Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 8 March 2016. Retrieved 9 November 2021.
    13. ↑ Rosenthal, Elisabeth (27 February 2016). "Ask Your Doctor if This Ad Is Right for You". The New York Times. Archived from the original on 31 January 2018. Retrieved 9 November 2021.
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