Chemistry:Apremilast

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Short description: Medication for psoriasis and psoriatic arthritis
Apremilast
Apremilast.svg
Apremilast molecule ball.png
Clinical data
Pronunciation/əˈprɛmɪlæst/ ə-PREM-i-last
Trade namesOtezla, Aplex, others
Other namesCC-10004
AHFS/Drugs.comMonograph
MedlinePlusa614022
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • UK: POM (Prescription only) [2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability73%;[3] Tmax = ~2.5 hours
Protein bindingc. 68%[3]
MetabolismLiver (CYP3A4, with minor contributions from CYP2A6, CYP1A2)[3]
MetabolitesO-desmethylapremilast glucuronide (and others)[4]
Elimination half-life6–9 hours[3]
ExcretionUrine (58%), faeces (39%)[3]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H24N2O7S
Molar mass460.50 g·mol−1
3D model (JSmol)

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.[6]

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.[6]

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.[7] 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.[7]

Apremilast has been studied as a treatment for alcohol-use disorder.[8][9]

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

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.[11][12]

Psychological

Worsening depression, suicidal thoughts, and other mood changes may occur with apremilast.[6]

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).[6]

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

Pharmacology

Mechanism of action

Apremilast is a small-molecule inhibitor of PDE4,[6] an enzyme that breaks down cyclic adenosine monophosphate (cAMP).[6] 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.[4]

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.[3][4]

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.[3][4]

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

Otezla is available in the US, but is dispensed only through a network of specialty pharmacies.[21] The estimated wholesale price is $22,500 for a year of treatment.[24] In Austria, the drug is available in all pharmacies, and a year of treatment costs health insurances about €11,000 as of 2018.[25] In India, the drug is available in all pharmacies, and a year of treatment costs about $268 or ₹22,000. Celgene made Otezla available in the U.K. in 2015.[26]

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

In 2020, Otezla generated US$2.2 billion for Amgen.[28]

Legal status

Apremilast was approved for use in the European Union in January 2015.[7]

Generic versions of the medication are available in Canada.[29] 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 [30]

See also

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". 21 June 2022. https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015. 
  2. ↑ "Otezla 30 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC)". 15 April 2020. https://www.medicines.org.uk/emc/product/3648/smpc. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/otezla-apremilast-999915#showall. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 (in de) Austria-Codex. Vienna: Österreichischer Apothekerverlag. 2015. 
  5. ↑ Apremilast
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 "Otezla- apremilast tablet, film coated Otezla- apremilast kit". 26 February 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6b1f516-4972-4d82-bced-113e47b41cc5. 
  7. ↑ 7.0 7.1 7.2 "Otezla EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/otezla.  This article incorporates text from this source, which is in the public domain.
  8. ↑ "Preclinical and clinical evidence for suppression of alcohol intake by apremilast". The Journal of Clinical Investigation 133 (6). March 2023. doi:10.1172/JCI159103. PMID 36656645. 
  9. ↑ "Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference". Alcoholism: Clinical and Experimental Research 42 (5): 926–938. May 2018. doi:10.1111/acer.13616. PMID 29469962. 
  10. ↑ "Apremilast (Otezla) Use During Pregnancy". 27 September 2019. https://www.drugs.com/pregnancy/apremilast.html. 
  11. ↑ "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. doi:10.3899/jrheum.140647. PMID 25593233. 
  12. ↑ "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. PMID 29462231. 
  13. ↑ "Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis". Drugs 74 (4): 423–441. March 2014. doi:10.1007/s40265-014-0191-y. PMID 24566842. 
  14. ↑ "Otezla Product Monograph". Celgene Corporation. http://www.celgenecanada.net/pdfs/Otezla_Product_Monograph_English_Version.pdf. 
  15. ↑ "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. doi:10.1177/1759720X19828669. PMID 30833991. 
  16. ↑ "Assessment report for Otezla". EMA. 20 November 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003746/WC500182629.pdf. 
  17. ↑ "Apremilast mechanism of action and application to psoriasis and psoriatic arthritis". Biochemical Pharmacology 83 (12): 1583–1590. June 2012. doi:10.1016/j.bcp.2012.01.001. PMID 22257911. 
  18. ↑ "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. doi:10.1111/j.1476-5381.2009.00559.x. PMID 20050849. 
  19. ↑ Liver cirrhosis : causes, diagnosis, and treatment. New York: Nova Biomedical Books. 2011. ISBN 978-1-61209-248-5. http://www.uaeh.edu.mx/sistema_investigacion/funciones/bajarArchivo_web.php?producto=4456&archivo=cirrosis_cap.pdf&fb_source=message. 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. http://www.utopharm.com/youchuo_en/news_sub.aspx?id=61. 
  21. ↑ 21.0 21.1 "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. 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. ↑ 24.0 24.1 Apremilast for the Treatment of Psoriatic Arthritis American College of Rheumatology (14 June 2014). Retrieved 29 October 2014.
  25. ↑ (in de) Warenverzeichnis. I. Vienna: Österreichischer Apothekerverlag. May 2018. p. 92. 
  26. ↑ "Celgene launches new psoriasis drug Otezla in UK". 24 May 2021. https://www.zenopa.com/news/801777078/celgene-launches-new-psoriasis-drug-otezla-in-uk. 
  27. ↑ "Amgen To Acquire Otezla For $13.4 Billion in Cash or Approximately $11.2 Billion Net of Anticipated Future Cash Tax Benefits". 26 August 2019. http://www.amgen.com/en/media/news-releases/2019/08/amgen-to-acquire-otezla-for-134-billion-in-cash-or-approximately-112-billion-net-of-anticipated-future-cash-tax-benefits. 
  28. ↑ "Amgen Reports Fourth Quarter And Full Year 2020 Financial Results". 2 February 2021. https://investors.amgen.com/news-releases/news-release-details/amgen-reports-fourth-quarter-and-full-year-2020-financial. 
  29. ↑ "Sandoz Canada launches PrSandoz® Apremilast". 14 November 2022. https://www.sandoz.ca/en/news/media-releases/sandoz-canada-launches-sandoz-apremilast-0. 
  30. ↑ Brittain, Brian (19 April 2023). "US Amgen ruling keeps generic psoriasis drug off market until 2028". https://www.reuters.com/legal/amgen-wins-appeal-us-patent-case-over-generic-psoriasis-drugs-2023-04-19/. 



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