Apremilast

Apremilast, brand name Otezla among others, is a medication for the treatment of certain types of psoriasis and psoriatic arthritis. It may also be useful for other immune system related inflammatory diseases. 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.[3] It is taken by mouth.

Apremilast
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
  • US: C (Risk not ruled out)
    Routes of
    administration    		by mouth (tablets)
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability73%;[1] Tmax = ~2.5 hours
    Protein bindingc. 68%[1]
    MetabolismLiver (CYP3A4, with minor contributions from CYP2A6, CYP1A2)[1]
    MetabolitesO-desmethylapremilast glucuronide (and others)[2]
    Elimination half-life6–9 hours[1]
    ExcretionUrine (58%), faeces (39%)[1]
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.234.786
    Chemical and physical data
    FormulaC22H24N2O7S
    Molar mass460.500 g/mol g·mol−1
    3D model (JSmol)

    Medical use

    Apremilast was approved by the United States Food and Drug Administration 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.[4][5][6] Apremilast is taken by mouth.[7]

    Contraindications

    In Europe, 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.[2] In the U.S., it may be used for pregnant women "if the potential benefit justifies the potential risk to the fetus".[8]

    Adverse effects

    Diarrhea and vomiting

    Diarrhea occurs in about 25% of patients taking apremilast. Severe gastrointestinal symptoms, when they occur, typically start within the first few weeks of treatment.[9][10]

    Psychological

    Worsening depression, suicidal thoughts, and other mood changes may occur with apremilast.[11]

    Weight loss

    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).[11]

    Other

    Common, usually mild to moderate adverse effects associated with apremilast include headache, back pain, nausea, diarrhea, fatigue, nasopharyngitis and upper respiratory tract infections.[12]

    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. It is not recommended to use simultaneously with strong P450 enzyme inducers, including rifampicin, phenobarbital, carbamazepine, phenytoin,[11] and St. John's Wort.[13]

    Pharmacology

    Mechanism of action

    Apremilast is a small molecule inhibitor of PDE4,[14] an enzyme that breaks down cyclic adenosine monophosphate (cAMP). 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 like 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.[2]

    Pharmacokinetics

    Apremilast is absorbed from the gut well (73%) and 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.[1][2]

    The 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 are found in the urine, and 7% in the feces.[1][2]

    Chemistry

    Apremilast is a phthalimide derivative. It is a white to pale yellow, non-hygroscopic 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 non-immune 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 form 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]

    Accessibility

    Otezla is available in the U.S., but is dispensed only through a network of specialty pharmacies.[4] The estimated wholesale price is $22,500 for a year of treatment.[7] In Austria, the drug is available in all pharmacies, and a year of treatment costs health insurances about €11,000.[21]

    See also

    References
    1. "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 March 2014.
    2. Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
    3. Apremilast
    4. "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.
    5. FDA approves Otezla to treat psoriatic arthritis
    6. "FDA Approves OTEZLA® (apremilast) for the Treatment of Oral Ulcers Associated with Behçet's Disease". ir.celgene.com. Retrieved 11 November 2019.
    7. Apremilast for the Treatment of Psoriatic Arthritis American College of Rheumatology (14 June 2014). Retrieved 29 October 2014.
    8. Drugs.com: Otezla Use During Pregnancy and Breastfeeding.
    9. 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): 479–88. doi:10.3899/jrheum.140647. PMID 25593233.
    10. 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.
    11. "Otezla (Prescribing Information)". Celgene Corporation, Summit, NJ; March 2014. Retrieved 29 October 2014.
    12. 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): 423–41. doi:10.1007/s40265-014-0191-y. PMC 3958815. PMID 24566842.
    13. "OTEZLA Product Monograph" (PDF). Celgene Canada. Celgene Corporation. Archived from the original (PDF) on 7 April 2015. Retrieved 3 April 2015.
    14. FDA Professional Drug Information for Otezla.
    15. Kragstrup TW, Adams M, Lomholt S, Nielsen MA, Heftdal LD, Schafer P, Deleuran B (2019). "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.
    17. Schafer P (June 2012). "Apremilast mechanism of action and application to psoriasis and psoriatic arthritis". Biochemical Pharmacology. 83 (12): 1583–90. 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): 842–55. 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.
    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. "Warenverzeichnis" (in German). I. Österreichischer Apothekerverlag. January 2016. Cite journal requires |journal= (help)
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