Apremilast

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Apremilast
Apremilast.svg
Systematic (IUPAC) name
N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
Clinical data
Trade names Otezla
AHFS/Drugs.com entry
MedlinePlus a614022
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 73%[1]
Protein binding 68%[1]
Metabolism Hepatic (CYP3A4, with minor contributions from CYP2A6, CYP1A2)[1]
Metabolites O-desmethylapremilast glucuronide (and others)[2]
Biological half-life 6–9 hours[1]
Excretion Urine (58%), faeces (39%)[1]
Identifiers
CAS Number 608141-41-9
ATC code L04AA32
PubChem CID 11561674
DrugBank DB05676
ChemSpider 9736448
UNII UP7QBP99PN
KEGG D08860
ChEBI CHEBI:78540
ChEMBL CHEMBL514800
Chemical data
Formula C22H24N2O7S
Molar mass 460.500 g/mol

Apremilast (brand name Otezla,[3] by Celgene) is a drug 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.[4] It is taken by mouth.

Medical use[edit]

Apremilast was approved by the United States Food and Drug Administration in March 2014 for treatment of adults with active psoriatic arthritis.[5] Apremilast is the first oral agent that is FDA-approved for the treatment of psoriatic arthritis and offers the convenience of oral dosing compared to treatment with biopharmaceuticals.[6] In September 2014, the US FDA approved apremilast for the treatment of moderate to severe plaque psoriasis.[7] It is also being tested for its efficacy in treating other chronic inflammatory diseases such as ankylosing spondylitis, Behcet's disease,[8] and rheumatoid arthritis.

Contraindications[edit]

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

Adverse effects[edit]

Common, usually mild to moderate adverse effects associated with apremilast include headache, back pain, nausea, diarrhea, fatigue, nasopharyngitis and upper respiratory tract infections.[10]

Other side effects include:

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

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. It is not recommended to use simultaneously with strong P450 enzyme inducers, including rifampicin, phenobarbital, carbamazepine, phenytoin,[11] and St. John's Wort.[12]

Pharmacology[edit]

Mechanism of action[edit]

Apremilast is a small molecule inhibitor of PDE4,[13] 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 the pro-inflammatory factors tumor necrosis factor alpha (TNFα), interleukin 17, interleukin 23, and many others, and up-regulates the anti-inflammatory interleukin 10. The importance of these individual factors for the clinical effect of apremilast is not clear.[2]

Pharmacokinetics[edit]

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 to) 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]

Physical and chemical properties[edit]

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 lipophilic solvents such as acetone, acetonitrile, butanone, dichloromethane, and tetrahydrofuran.[14]

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. Utopharm reported another more thermodynamically stable anhydrous crystal form II than the crystal form B.[15]

Accessibility[edit]

Otezla is available in the US, but is dispensed only through a network of specialty pharmacies.[7] The estimated wholesale price is $22,500 for a year of treatment.[6] In Austria, the drug is available in all pharmacies, and a year of treatment costs health insurances about €11,000.[16]

See also[edit]

References[edit]

  1. ^ a b c d e f g "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 March 2014. 
  2. ^ a b c d e Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. 
  3. ^ "Celgene Corporation Announces 2014 Financial Outlook and Preliminary 2013 Results" (Press release). Celgene Corporation. 13 January 2014. Retrieved 2014-01-21. 
  4. ^ Apremilast
  5. ^ FDA approves Otezla to treat psoriatic arthritis
  6. ^ a b Apremilast for the Treatment of Psoriatic Arthritis American College of Rheumatology (14 June 2014). Retrieved 29 October 2014.
  7. ^ 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.
  8. ^ Hatemi, Gulen; Melikoglu, Melike; Tunc, Recep; Korkmaz, Cengiz; Turgut Ozturk, Banu; Mat, Cem; Merkel, Peter A.; Calamia, Kenneth T.; Liu, Ziqi; Pineda, Lilia; Stevens, Randall M.; Yazici, Hasan; Yazici, Yusuf (2015). "Apremilast for Behçet's Syndrome — A Phase 2, Placebo-Controlled Study". New England Journal of Medicine 372 (16): 1510. doi:10.1056/NEJMoa1408684. PMID 25875256. 
  9. ^ Drugs.com: Otezla Use During Pregnancy and Breastfeeding.
  10. ^ Mease, PJ; Armstrong, AW (25 February 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. PMID 24566842. 
  11. ^ a b c "Otezla (Prescribing Information)". Celgene Corporation, Summit, NJ; March 2014. Retrieved 29 October 2014.
  12. ^ "OTEZLA Product Monograph" (PDF). Celgene Canada. Celgene Corporation. Retrieved 3 April 2015. 
  13. ^ FDA Professional Drug Information for Otezla.
  14. ^ "Assessment report for Otezla" (PDF). EMA. 20 November 2014. 
  15. ^ "A novel stable and non-solvate crystal form II on Apremilast and processes for the preparation thereof". Utopharm. 2015-04-18. 
  16. ^ "Warenverzeichnis" (in German) I. Österreichischer Apothekerverlag. January 2016.