Apremilast

Last updated

Apremilast
Apremilast.svg
Apremilast molecule ball.png
Clinical data
Pronunciation /əˈprɛmɪlæst/ ə-PREM-i-last
Trade names Otezla, others
Other namesCC-10004
AHFS/Drugs.com Monograph
MedlinePlus a614022
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1] [2]
  • UK: POM (Prescription only) [3]
  • US: ℞-only
  • EU:Rx-only [4]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 73%; [5] Tmax = ~2.5 hours
Protein binding c. 68% [5]
Metabolism Liver (CYP3A4, with minor contributions from CYP2A6, CYP1A2) [5]
Metabolites O-desmethylapremilast glucuronide (and others) [6]
Elimination half-life 6–9 hours [5]
Excretion Urine (58%), faeces (39%) [5]
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 InfoCard 100.234.786 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H24N2O7S
Molar mass 460.50 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. 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. [7] It is taken by mouth. [8]

Contents

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. [8]

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. [4] 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. [4]

Apremilast has been studied as a treatment for alcohol-use disorder. [9] [10]

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. [6] In the U.S., it may be used for pregnant women "if the potential benefit justifies the potential risk to the fetus". [11]

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. [12] [13]

Psychological

Worsening depression, suicidal thoughts, and other mood changes may occur with apremilast. [8]

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). [8]

Other

Common, usually mild to moderate adverse effects associated with apremilast include headache, back pain, nausea, diarrhoea, fatigue, nasopharyngitis, and upper respiratory tract infections. [14]

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, [8] and St. John's wort is not recommended. [15]

Pharmacology

Mechanism of action

Apremilast is a small-molecule inhibitor of PDE4, [8] an enzyme that breaks down cyclic adenosine monophosphate (cAMP). [8] 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. [16] The importance of these individual factors for the clinical effect of apremilast is not clear. [6]

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. [5] [6]

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. [5] [6]

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. [17]

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. [18] [19] The inhibition potency of apremilast in TNF-α production is similar to lenalidomide. [20]

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. [21]

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. [22] [23] [24] Apremilast is taken by mouth. [25]

Society and culture

Economics

Apremilast is available in the US, but is dispensed only through a network of specialty pharmacies. [22] The estimated wholesale price is US$22,500 for a year of treatment. [25] In Austria, a year of treatment costs health insurances about €11,000 as of 2018. [26] In India, a year of treatment costs about $268 or ₹22,000.[ citation needed ] Celgene made Otezla available in the UK in 2015. [27]

In 2019, Amgen acquired Otezla from Celgene for $13.4 billion. [28] [29]

In 2020, Otezla generated $2.2 billion for Amgen. [30]

Apremilast was approved for use in the European Union in January 2015. [4]

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. [33]

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Psoriasis</span> Skin disease

Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete body coverage. Injury to the skin can trigger psoriatic skin changes at that spot, which is known as the Koebner phenomenon.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autommune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

<span class="mw-page-title-main">Psoriatic arthritis</span> Long-term inflammatory arthritis

Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It has US Food and Drug Administration (FDA) approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Tumor necrosis factor alpha (TNFα) is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It is administered by subcutaneous injection. It works by inactivating tumor necrosis factor-alpha (TNFα).

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

Biological response modifiers (BRMs) are substances that modify immune responses. They can be endogenous or exogenous, and they can either enhance an immune response or suppress it. Some of these substances arouse the body's response to an infection, and others can keep the response from becoming excessive. Thus they serve as immunomodulators in immunotherapy, which can be helpful in treating cancer and in treating autoimmune diseases, such as some kinds of arthritis and dermatitis. Most BRMs are biopharmaceuticals (biologics), including monoclonal antibodies, interleukin 2, interferons, and various types of colony-stimulating factors. "Immunotherapy makes use of BRMs to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer", whereas BRMs for rheumatoid arthritis aim to reduce inflammation.

Ustekinumab, sold under the brand name Stelara among others, is a monoclonal antibody medication developed by Janssen Pharmaceuticals, for the treatment of Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23.

<span class="mw-page-title-main">Golimumab</span> Pharmaceutical drug

Golimumab, sold under the brand name Simponi, is a human monoclonal antibody which is used as an immunosuppressive medication. Golimumab targets tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory molecule and hence is a TNF inhibitor. Profound reduction in C-reactive protein (CRP) levels, interleukin (IL)-6, intercellaular adhesion molecules (ICAM)-1, matrix metalloproteinase (MMP)-3, and vascular endothelial growth factor (VEGF) demonstrates golimumab as an effective modulator of inflammatory markers and bone metabolism. Golimumab is given via subcutaneous injection.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

<span class="mw-page-title-main">Phosphodiesterase-4 inhibitor</span> Class of chemical compounds

A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

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<span class="mw-page-title-main">Secukinumab</span> Monoclonal antibody against IL-17

Secukinumab, sold under the brand name Cosentyx among others, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis.

Guselkumab, sold under the brand name Tremfya, is a monoclonal antibody against interleukin-23 used for the treatment of plaque psoriasis.

Risankizumab, sold under the brand name Skyrizi, is a humanized monoclonal antibody used for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. It is designed to target interleukin 23A (IL-23A). It is given by subcutaneous injection.

Bimekizumab, sold under the brand name Bimzelx, is a humanized anti-IL17A, anti-IL-17F, and anti-IL17AF monoclonal antibody that is used to treat plaque psoriasis, psoriatic arthritis, axial spondyloarthritis, and ankylosing spondylitis.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ↑ https://www.tga.gov.au/resources/auspar/auspar-apremilast
  3. ↑ "Otezla 30 mg Film-Coated Tablets – Summary of Product Characteristics (SmPC)". (emc). 15 April 2020. Retrieved 19 April 2020.
  4. 1 2 3 4 "Otezla EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 19 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. 1 2 3 4 5 6 7 "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 March 2014.
  6. 1 2 3 4 5 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  7. ↑ Apremilast
  8. 1 2 3 4 5 6 7 "Otezla- apremilast tablet, film coated Otezla- apremilast kit". DailyMed. 26 February 2020. Retrieved 19 April 2020.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ "Apremilast (Otezla) Use During Pregnancy". Drugs.com. 27 September 2019. Retrieved 19 April 2020.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ "Otezla Product Monograph" (PDF). Celgene Canada. Celgene Corporation. Archived from the original (PDF) on 7 April 2015. Retrieved 3 April 2015.
  16. ↑ 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.
  17. ↑ "Assessment report for Otezla" (PDF). EMA. 20 November 2014.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ "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.
  22. 1 2 "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.
  23. ↑ "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  24. ↑ "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.
  25. 1 2 "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.
  26. ↑ Warenverzeichnis (in German). Vol. I. Vienna: Österreichischer Apothekerverlag. May 2018. p. 92.
  27. ↑ "Celgene launches new psoriasis drug Otezla in UK". 24 May 2021. Retrieved 24 May 2021.
  28. ↑ "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.
  29. ↑ "Amgen Completes Acquisition Of Otezla (apremilast)". Amgen (Press release). 21 November 2019. Retrieved 23 February 2024.
  30. ↑ "Amgen Reports Fourth Quarter And Full Year 2020 Financial Results". Amgen, Inc (Press release). 2 February 2021. Retrieved 2 February 2021.
  31. ↑ "Sandoz Canada launches PrSandoz Apremilast". Sandoz Canada. 14 November 2022. Retrieved 18 August 2023.
  32. ↑ Brittain B (19 April 2023). "US Amgen ruling keeps generic psoriasis drug off market until 2028". Reuters. Retrieved 18 August 2023.
  33. 1 2 "Apremilast Accord EPAR". European Medicines Agency (EMA). 22 February 2024. Retrieved 23 February 2024.
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