|Systematic (IUPAC) name|
|Metabolism||Hepatic (CYP3A4, with minor contributions from CYP2A6, CYP1A2)|
|Metabolites||O-desmethylapremilast glucuronide (and others)|
|Biological half-life||6–9 hours|
|Excretion||Urine (58%), faeces (39%)|
|Molar mass||460.500 g/mol|
Apremilast (brand name Otezla, 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. It is taken by mouth.
Apremilast was approved by the United States Food and Drug Administration in March 2014 for treatment of adults with active psoriatic arthritis. 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. In September 2014, the US FDA approved apremilast for the treatment of moderate to severe plaque psoriasis. It is also being tested for its efficacy in treating other chronic inflammatory diseases such as ankylosing spondylitis, Behcet's disease, and rheumatoid arthritis.
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. In the US, it may be used for pregnant women "if the potential benefit justifies the potential risk to the fetus".
Other side effects include:
- Depression: Worsening depression, suicidal thoughts, and other mood changes may occur with apremilast.
- 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).
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, and St. John's Wort.
Mechanism of action
Apremilast is a small molecule inhibitor of PDE4, 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.
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.
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.
Physical and chemical properties
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.
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.
Otezla is available in the US, but is dispensed only through a network of specialty pharmacies. The estimated wholesale price is $22,500 for a year of treatment. In Austria, the drug is available in all pharmacies, and a year of treatment costs health insurances about €11,000.
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