Apremilast

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. Apremilast, similar to methotrexate, is taken by mouth.

It is in clinical trials for the treatment of ankylosing spondylitis, Behçet's disease, atopic dermatitis, and ulcerative colitis.

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

Adverse effects

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

Other side effects include:

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, 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.

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.

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.

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.

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.

Accessibility

Otezla is available in the U.S., 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.