Apremilast

Apremilast
Clinical data
Pronunciation/əˈprɛmɪlæst/ ə-PREM-i-last
Trade namesOtezla, others
Other namesCC-10004
AHFS/Drugs.comMonograph
MedlinePlusa614022
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability73%;[8] Tmax = ~2.5 hours
Protein bindingc. 68%[8]
MetabolismLiver (CYP3A4, with minor contributions from CYP2A6, CYP1A2)[8]
MetabolitesO-desmethylapremilast glucuronide (and others)[9]
Elimination half-life6–9 hours[8]
ExcretionUrine (58%), faeces (39%)[8]
Identifiers
  • N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.234.786 Edit this at Wikidata
Chemical and physical data
FormulaC22H24N2O7S
Molar mass460.50 g·mol−1
3D model (JSmol)
  • O=S(=O)(C)C[C@H](c1ccc(OC)c(OCC)c1)N3C(=O)c2cccc(c2C3=O)NC(=O)C
  • InChI=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
  • Key: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.[4] The drug acts as a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4).[4] It is taken by mouth.[4]

Medical uses

[edit]

Apremilast is indicated in the United States for the treatment of adults with active psoriatic arthritis, people with plaque psoriasis who are candidates for phototherapy or systemic therapy, and adults with oral ulcers associated with Behçet's disease.[4]

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.[6] 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.[6]

Contraindications

[edit]

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.[9] In the US, it may be used for pregnant women "if the potential benefit justifies the potential risk to the fetus".[10]

Adverse effects

[edit]

Diarrhea and vomiting

[edit]

Diarrhea occurs in about 25% of people taking apremilast. Severe gastrointestinal symptoms, when they occur, typically start within the first few weeks of treatment.[11][12]

Psychological

[edit]

Worsening depression, suicidal thoughts, and other mood changes may occur with apremilast.[4]

Weight loss

[edit]

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).[4]

Other

[edit]

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

[edit]

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,[4] and St. John's wort is not recommended.[14]

Pharmacology

[edit]

Mechanism of action

[edit]

Apremilast is a small-molecule inhibitor of PDE4,[4] an enzyme that breaks down cyclic adenosine monophosphate (cAMP).[4] 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.[9]

Pharmacokinetics

[edit]

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.[8][9]

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.[8][9]

Chemistry

[edit]

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

[edit]

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

[edit]

Economics

[edit]

Apremilast is available in the US, but is dispensed only through a network of specialty pharmacies.[21] The estimated wholesale price is US$22,500 for a year of treatment.[24] In Austria, a year of treatment costs health insurances about €11,000 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]

Apremilast was listed on the PBS in Australia in January 2021, for chronic plaque psoriasis.[30] As of October 2024, the cost to the Australian government for a year of treatment is about $8500, and the cost to consumer is about $400.[31]

[edit]

Apremilast was approved for use in the European Union in January 2015.[6]

Generic versions of the medication are available in Canada.[32] 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.[33] 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.[7] The applicant for this medicinal product is Accord Healthcare S.L.U.[7] Apremilast Accord was approved for medical use in the European Union in April 2024.[7]

Research

[edit]

Apremilast has been studied as a treatment for alcohol-use disorder.[34][35]

References

[edit]
  1. ^ a b "AusPAR: Apremilast". Therapeutic Goods Administration (TGA).
  2. ^ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  3. ^ "Otezla 30 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC)". (emc). 15 April 2020. Retrieved 19 April 2020.
  4. ^ a b c d e f g h i j "Otezla- apremilast tablet, film coated Otezla- apremilast kit". DailyMed. 26 February 2020. Retrieved 19 April 2020.
  5. ^ "Otezla- apremilast kit; Otezla- apremilast tablet, film coated". DailyMed. 5 February 2021. Retrieved 17 October 2024.
  6. ^ a b c d "Otezla EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 19 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ a b c d "Apremilast Accord EPAR". European Medicines Agency (EMA). 22 February 2024. Retrieved 23 February 2024.
  8. ^ a b c d e f g "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 March 2014.
  9. ^ a b c d e Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  10. ^ "Apremilast (Otezla) Use During Pregnancy". Drugs.com. 27 September 2019. Retrieved 19 April 2020.
  11. ^ Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, et al. (March 2015). "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. doi:10.3899/jrheum.140647. PMID 25593233.
  12. ^ Stein Gold L, Bagel J, Lebwohl M, Jackson JM, Chen R, Goncalves J, et al. (February 2018). "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. PMID 29462231.
  13. ^ Mease PJ, Armstrong AW (March 2014). "Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis". Drugs. 74 (4): 423–441. doi:10.1007/s40265-014-0191-y. PMC 3958815. PMID 24566842.
  14. ^ "Otezla Product Monograph" (PDF). Archived (PDF) from the original on 7 April 2015. Retrieved 3 April 2015.
  15. ^ Kragstrup TW, Adams M, Lomholt S, Nielsen MA, Heftdal LD, Schafer P, et al. (2019). "IL-12/IL-23p40 identified as a downstream target of apremilast in ex vivo models of arthritis". Therapeutic Advances in Musculoskeletal Disease. 11: 1759720X19828669. doi:10.1177/1759720X19828669. PMC 6391542. PMID 30833991.
  16. ^ "Assessment report for Otezla" (PDF). EMA. 20 November 2014. Archived from the original (PDF) on 17 June 2018. Retrieved 22 January 2016.
  17. ^ Schafer P (June 2012). "Apremilast mechanism of action and application to psoriasis and psoriatic arthritis". Biochemical Pharmacology. 83 (12): 1583–1590. doi:10.1016/j.bcp.2012.01.001. PMID 22257911.
  18. ^ Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al. (February 2010). "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. doi:10.1111/j.1476-5381.2009.00559.x. PMC 2829210. PMID 20050849.
  19. ^ Michelli ML (2011). Liver cirrhosis : causes, diagnosis, and treatment. New York: Nova Biomedical Books. ISBN 978-1-61209-248-5. Archived from the original on 4 March 2016. Retrieved 26 July 2018.
  20. ^ "A novel stable and non-solvate crystal form II on Apremilast and processes for the preparation thereof". Utopharm. 18 April 2015. Archived from the original on 31 May 2015.
  21. ^ a b "Oral Otezla (apremilast) Approved by the U.S. Food and Drug Administration for the Treatment of Patients with Moderate to Severe Plaque Psoriasis" (Press release). Celgene Corporation. 23 September 2014. Retrieved 29 October 2014.
  22. ^ "FDA approves Otezla to treat psoriatic arthritis". U.S. Food and Drug Administration (FDA) (Press release). 21 March 2014. Archived from the original on 13 February 2017. Retrieved 19 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  23. ^ "FDA Approves Otezla (apremilast) for the Treatment of Oral Ulcers Associated with Behçet's Disease". Celgene Corporation (Press release). 19 July 2019. Archived from the original on 20 April 2020. Retrieved 11 November 2019.
  24. ^ a b "Apremilast for the Treatment of Psoriatic Arthritis". American College of Rheumatology. 14 June 2014. Archived from the original on 21 February 2015. Retrieved 29 October 2014.
  25. ^ Warenverzeichnis (in German). Vol. I. Vienna: Österreichischer Apothekerverlag. May 2018. p. 92.
  26. ^ "Celgene launches new psoriasis drug Otezla in UK". 24 May 2021. Archived from the original on 24 May 2021. Retrieved 24 May 2021.
  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 (Press release). 26 August 2019. Archived from the original on 7 October 2021. Retrieved 19 April 2020.
  28. ^ "Amgen Completes Acquisition Of Otezla (apremilast)". Amgen (Press release). 21 November 2019. Retrieved 23 February 2024.
  29. ^ "Amgen Reports Fourth Quarter And Full Year 2020 Financial Results". Amgen, Inc (Press release). 2 February 2021. Retrieved 2 February 2021.
  30. ^ "PBS Drug utilisation sub committee report September 2023". Retrieved 16 October 2024.
  31. ^ "PBS listing for Apremilast". Retrieved 16 October 2024.
  32. ^ "Sandoz Canada launches PrSandoz Apremilast". Sandoz Canada. 14 November 2022. Retrieved 18 August 2023.
  33. ^ Brittain B (19 April 2023). "US Amgen ruling keeps generic psoriasis drug off market until 2028". Reuters. Retrieved 18 August 2023.
  34. ^ Grigsby KB, Mangieri RA, Roberts AJ, Lopez MF, Firsick EJ, Townsley KG, et al. (March 2023). "Preclinical and clinical evidence for suppression of alcohol intake by apremilast". The Journal of Clinical Investigation. 133 (6). doi:10.1172/JCI159103. PMC 10014105. PMID 36656645.
  35. ^ Blednov YA, Da Costa AJ, Tarbox T, Ponomareva O, Messing RO, Harris RA (May 2018). "Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference". Alcoholism: Clinical and Experimental Research. 42 (5): 926–938. doi:10.1111/acer.13616. PMC 5915912. PMID 29469962.
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