Apremilast Explained

Width:215
Width2:215
Tradename:Otezla, others
Dailymedid:Apremilast
Pregnancy Au:B3
Routes Of Administration:By mouth
Atc Prefix:L04
Atc Suffix:AA32
Legal Au:S4
Legal Au Comment:[1] [2]
Legal Uk:POM
Legal Uk Comment:[3]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Status:Rx-only
Bioavailability:73%;[4] Tmax = ~2.5 hours
Protein Bound:c. 68%
Metabolism:Liver (CYP3A4, with minor contributions from CYP2A6, CYP1A2)
Metabolites:O-desmethylapremilast glucuronide (and others)
Elimination Half-Life:6–9 hours
Excretion:Urine (58%), faeces (39%)
Cas Number:608141-41-9
Pubchem:11561674
Drugbank:DB05676
Chemspiderid:9736448
Unii:UP7QBP99PN
Kegg:D08860
Chebi:78540
Chembl:514800
Synonyms:CC-10004
Iupac Name:N-acetamide
C:22
H:24
N:2
O:7
S:1
Smiles:O=S(=O)(C)C[C@H](c1ccc(OC)c(OCC)c1)N3C(=O)c2cccc(c2C3=O)NC(=O)C
Stdinchi:1S/C22H24N2O7S/c1-5-31-19-11-14(9-10-18(19)30-3)17(12-32(4,28)29)24-21(26)15-7-6-8-16(23-13(2)25)20(15)22(24)27/h6-11,17H,5,12H2,1-4H3,(H,23,25)/t17-/m1/s1
Stdinchikey:IMOZEMNVLZVGJZ-QGZVFWFLSA-N

Apremilast, sold under the brand name Otezla among others, is a medication for the treatment of certain types of psoriasis and psoriatic arthritis. The drug acts as a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4) and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells.[5] It is taken by mouth.

Medical uses

Apremilast is indicated in the United States for the treatment of adults with active psoriatic arthritis, adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy, and adults with oral ulcers associated with Behçet's disease.

In the European Union, apremilast alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adults who have had an inadequate response or who have been intolerant to a prior DMARD therapy. It is also indicated for the treatment of moderate to severe chronic plaque psoriasis in adults who failed to respond to, have a contraindication to, or are intolerant of other systemic therapies, including cyclosporine, methotrexate, or psoralen and ultraviolet-A light.

Apremilast has been studied as a treatment for alcohol-use disorder.[6] [7]

Contraindications

In the European Union, the drug is contraindicated during pregnancy because mice and monkeys receiving very high doses of apremilast have been observed to suffer miscarriages and other pregnancy problems.[8] In the U.S., it may be used for pregnant women "if the potential benefit justifies the potential risk to the fetus".[9]

Adverse effects

Diarrhea and vomiting

Diarrhea occurs in about 25% of people taking apremilast. Severe gastrointestinal symptoms, when they occur, typically start within the first few weeks of treatment.[10] [11]

Psychological

Worsening depression, suicidal thoughts, and other mood changes may occur with apremilast.[12]

Weight loss

Weight loss has been associated with apremilast. Reports from clinical studies indicated a 5 to 10% decrease in body weight in 10% of patients taking apremilast (compared to 3.3% of patients taking placebo).[12]

Other

Common, usually mild to moderate adverse effects associated with apremilast include headache, back pain, nausea, diarrhoea, fatigue, nasopharyngitis, and upper respiratory tract infections.[13]

Interactions

Concurrent use of strong cytochrome P450 enzyme inducers has been shown to decrease exposure of apremilast and can result in reduced or loss of efficacy of apremilast. Using it simultaneously with strong P450 enzyme inducers, including rifampicin, phenobarbital, carbamazepine, phenytoin,[12] and St. John's wort is not recommended.[14]

Pharmacology

Mechanism of action

Apremilast is a small-molecule inhibitor of PDE4,[12] an enzyme that breaks down cyclic adenosine monophosphate (cAMP).[12] In inflammatory cells, PDE4 is the dominant enzyme responsible for this reaction. The resulting increase in cAMP levels down-regulates expression of a number of pro-inflammatory factors such as tumor necrosis factor alpha (TNFα), interleukin 17, interleukin 23, and many others, and up-regulates the anti-inflammatory interleukin 10. In ex vivo models of arthritis, IL-12/IL-23p40 was specifically identified as a downstream target of apremilast.[15] The importance of these individual factors for the clinical effect of apremilast is not clear.

Pharmacokinetics

Apremilast is absorbed well from the gut (73%), independently of food intake, and reaches peak blood plasma concentrations after 2.5 hours. Plasma protein binding is 68%. It is metabolised in the liver, mainly via the enzyme CYP3A4, but to a minor extent via CYP1A2 and CYP2A6. The main metabolite is O-desmethylapremilast glucuronide.

Its half-life is 6–9 hours. The substance is eliminated through the kidney (58%) and feces (39%), mainly in form of its metabolites. Only 3% of the original substance is found in the urine, and 7% in the feces.

Chemistry

Apremilast is a phthalimide derivative. It is a white to pale yellow, nonhygroscopic powder that is practically insoluble in water and buffer solutions in a wide pH range, but is soluble in lipophilic solvents such as acetone, acetonitrile, butanone, dichloromethane, and tetrahydrofuran.[16]

In vitro, apremilast reduces PDE4 activity, leading to an increase in cyclic-adenosine monophosphate (cAMP) concentrations in immune and nonimmune cell types, partially inhibiting the production of many pro-inflammatory cytokines, such as TNF-α, IFN-γ IL-2, IL-12, and IL-23 and elevating the production of the anti-inflammatory cytokine IL-10.[17] [18] The inhibition potency of apremilast in TNF-α production is similar to lenalidomide.[19]

Celgene reported seven kinds of crystal forms — A, B, C, D, E, F, and G — and thought the crystal form B was the most thermodynamically stable anhydrous form. However, Utopharm reported another more thermodynamically stable anhydrous crystal form II than the crystal form B.[20]

History

Apremilast was approved by the US Food and Drug Administration (FDA) in 2014, for treatment of adults with active psoriatic arthritis and moderate to severe plaque psoriasis, and approved in 2019, for oral ulcers associated with Behçet's disease.[21] [22] [23] Apremilast is taken by mouth.[24]

Society and culture

Economics

Apremilast is available in the US, but is dispensed only through a network of specialty pharmacies.[21] The estimated wholesale price is for a year of treatment.[24] In Austria, a year of treatment costs health insurances about as of 2018.[25] Celgene made Otezla available in the UK in 2015.[26]

In 2019, Amgen acquired Otezla from Celgene for $13.4 billion.[27] [28]

In 2020, Otezla generated $2.2 billion for Amgen.[29]

Legal status

Apremilast was approved for use in the European Union in January 2015.[30]

Generic versions of the medication are available in Canada.[31] In April 2023, an American court case confirmed Amgen's patents on Otezla until 2028, delaying the introduction of generics until at least that date.[32] In February 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Apremilast Accord, intended for the treatment of psoriatic arthritis, psoriasis and Behcet's disease.[33] The applicant for this medicinal product is Accord Healthcare S.L.U.

Notes and References

  1. Web site: Prescription medicines: registration of new chemical entities in Australia, 2015 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 10 April 2023.
  2. https://www.tga.gov.au/resources/auspar/auspar-apremilast
  3. Web site: Otezla 30 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC) . (emc) . 15 April 2020 . 19 April 2020.
  4. Web site: Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. 28 March 2014.
  5. http://www.adooq.com/apremilast-cc-10004.html Apremilast
  6. Grigsby KB, Mangieri RA, Roberts AJ, Lopez MF, Firsick EJ, Townsley KG, Beneze A, Bess J, Eisenstein TK, Meissler JJ, Light JM, Miller J, Quello S, Shadan F, Skinner M, Aziz HC, Metten P, Morrisett RA, Crabbe JC, Roberto M, Becker HC, Mason BJ, Ozburn AR . Preclinical and clinical evidence for suppression of alcohol intake by apremilast . The Journal of Clinical Investigation . 133 . 6 . March 2023 . 36656645 . 10014105 . 10.1172/JCI159103 .
  7. Blednov YA, Da Costa AJ, Tarbox T, Ponomareva O, Messing RO, Harris RA . Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference . Alcoholism: Clinical and Experimental Research . 42 . 5 . 926–938 . May 2018 . 29469962 . 5915912 . 10.1111/acer.13616 .
  8. Book: Austria-Codex. Haberfeld H . Österreichischer Apothekerverlag . Vienna . 2015 . de.
  9. Web site: Apremilast (Otezla) Use During Pregnancy . Drugs.com . 27 September 2019 . 19 April 2020.
  10. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, Hochfeld M, Teng LL, Schett G, Lespessailles E, Hall S . Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis . The Journal of Rheumatology . 42 . 3 . 479–488 . March 2015 . 25593233 . 10.3899/jrheum.140647 . free .
  11. Stein Gold L, Bagel J, Lebwohl M, Jackson JM, Chen R, Goncalves J, Levi E, Duffin KC . Efficacy and Safety of Apremilast in Systemic- and Biologic-Naive Patients With Moderate Plaque Psoriasis: 52-Week Results of UNVEIL . Journal of Drugs in Dermatology . 17 . 2 . 221–228 . February 2018 . 29462231 .
  12. Web site: Otezla- apremilast tablet, film coated Otezla- apremilast kit . DailyMed . 26 February 2020 . 19 April 2020.
  13. Mease PJ, Armstrong AW . Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis . Drugs . 74 . 4 . 423–441 . March 2014 . 24566842 . 3958815 . 10.1007/s40265-014-0191-y .
  14. Web site: Otezla Product Monograph. Celgene Canada. Celgene Corporation. 3 April 2015. https://web.archive.org/web/20150407204756/http://www.celgenecanada.net/pdfs/Otezla_Product_Monograph_English_Version.pdf. 7 April 2015. dead.
  15. Kragstrup TW, Adams M, Lomholt S, Nielsen MA, Heftdal LD, Schafer P, Deleuran B . IL-12/IL-23p40 identified as a downstream target of apremilast in ex vivo models of arthritis . Therapeutic Advances in Musculoskeletal Disease . 11 . 1759720X19828669 . 2019 . 30833991 . 6391542 . 10.1177/1759720X19828669 .
  16. Web site: Assessment report for Otezla. EMA. 20 November 2014. 22 January 2016. 17 June 2018. https://web.archive.org/web/20180617204050/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003746/WC500182629.pdf. dead.
  17. Schafer P . Apremilast mechanism of action and application to psoriasis and psoriatic arthritis . Biochemical Pharmacology . 83 . 12 . 1583–1590 . June 2012 . 22257911 . 10.1016/j.bcp.2012.01.001 .
  18. Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, Bartlett JB, Loveland MA, Gilhar A, Cheung YF, Baillie GS, Houslay MD, Man HW, Muller GW, Stirling DI . Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis . British Journal of Pharmacology . 159 . 4 . 842–855 . February 2010 . 20050849 . 2829210 . 10.1111/j.1476-5381.2009.00559.x .
  19. Book: Michelli ML. Liver cirrhosis : causes, diagnosis, and treatment. Nova Biomedical Books. New York. 978-1-61209-248-5. 2011. 26 July 2018. 4 March 2016. https://web.archive.org/web/20160304090053/http://www.uaeh.edu.mx/sistema_investigacion/funciones/bajarArchivo_web.php?producto=4456&archivo=cirrosis_cap.pdf&fb_source=message. dead.
  20. Web site: A novel stable and non-solvate crystal form II on Apremilast and processes for the preparation thereof . Utopharm . 18 April 2015 . dead . https://web.archive.org/web/20150531020846/http://www.utopharm.com/youchuo_en/news_sub.aspx?id=61 . 31 May 2015 .
  21. http://ir.celgene.com/releasedetail.cfm?releaseid=872240 "Oral Otezla (apremilast) Approved by the U.S. Food and Drug Administration for the Treatment of Patients with Moderate to Severe Plaque Psoriasis"
  22. FDA approves Otezla to treat psoriatic arthritis . U.S. Food and Drug Administration (FDA) . 21 March 2014 . https://web.archive.org/web/20170213211338/https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm390091.htm . 13 February 2017 . dead . 19 April 2020.
  23. FDA Approves Otezla (apremilast) for the Treatment of Oral Ulcers Associated with Behçet's Disease . Celgene Corporation . 19 July 2019 . 11 November 2019 . https://web.archive.org/web/20200420032909/https://ir.celgene.com/press-releases-archive/press-release-details/2019/FDA-Approves-OTEZLA-apremilast-for-the-Treatment-of-Oral-Ulcers-Associated-with-Behets-Disease/ . 20 April 2020 . live .
  24. Web site: Apremilast for the Treatment of Psoriatic Arthritis . American College of Rheumatology . 14 June 2014 . https://web.archive.org/web/20150221195556/http://www.rheumatology.org/Publications/Hotline/Apremilast_for_the_Treatment_of_Psoriatic_Arthritis/ . 21 February 2015 . dead . 29 October 2014.
  25. Book: Warenverzeichnis. I. 92. May 2018. Österreichischer Apothekerverlag. Vienna. de.
  26. Web site: Celgene launches new psoriasis drug Otezla in UK. 24 May 2021. 24 May 2021. 24 May 2021. https://web.archive.org/web/20210524192944/https://www.zenopa.com/news/801777078/celgene-launches-new-psoriasis-drug-otezla-in-uk. dead.
  27. Amgen To Acquire Otezla For $13.4 Billion in Cash or Approximately $11.2 Billion Net of Anticipated Future Cash Tax Benefits . Amgen, Inc . 26 August 2019 . 19 April 2020 . 7 October 2021 . https://web.archive.org/web/20211007133537/https://www.amgen.com/newsroom/press-releases/2019/08/amgen-to-acquire-otezla-for-134-billion-in-cash-or-approximately-112-billion-net-of-anticipated-future-cash-tax-benefits . live .
  28. Amgen Completes Acquisition Of Otezla (apremilast) . Amgen . 21 November 2019 . 23 February 2024.
  29. Amgen Reports Fourth Quarter And Full Year 2020 Financial Results . Amgen, Inc . 2 February 2021 . 2 February 2021.
  30. Web site: Otezla EPAR . European Medicines Agency (EMA) . 17 September 2018 . 19 April 2020.
  31. Web site: Sandoz Canada launches PrSandoz Apremilast . 14 November 2022 . Sandoz Canada . 18 August 2023 .
  32. Web site: US Amgen ruling keeps generic psoriasis drug off market until 2028. Brittain . Brian . 19 April 2023 . Reuters . 18 August 2023 .
  33. Web site: Apremilast Accord EPAR . European Medicines Agency (EMA) . 22 February 2024 . 23 February 2024.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Apremilast".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.