Apremilast

Apremilast (CC-10004) is an orally available inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4) with an IC₅₀ of 74 nM. Apremilast inhibits TNF-α release by lipopolysaccharide (LPS) with an IC₅₀ of 104 nM^[1]. IC50 & Target: IC50: 74 nM (PDE4) and 104 nM (TNF-α)^[1] In Vitro: Apremilast (CC-10004) inhibits TNF-α release by lipopolysaccharide (LPS) with an IC₅₀ of 104 nM (pIC₅₀=6.98±0.2), which almost exactly replicates previous reported TNF-α inhibition by Apremilast on peripheral blood mononuclear cells (PBMCs) (IC₅₀=110 nM) and which is similar to the potency of Apremilast for PDE4 enzymatic inhibition (IC₅₀=74 nM). These results are clearly consistent with the hypothesis that Apremilast inhibits TNF-α by increasing intracellular cAMP levels. PKA, Epac1 and Epac2 knockdowns prevented TNF-α inhibition and IL-10 stimulation by Apremilast^[1]. In Vivo: Apremilast (CC-10004), orally administered (5 mg/kg), significantly inhibits TNF-α production in the air pouch by 39 % (61±6 % of vehicle, P <0.001) and diminishes (by 28 %) the number of leukocytes present (72±12 % of vehicle, P<0.05). In agreement, immunohistologic analysis shows that neutrophil accumulation in the air pouch membrane is dramatically reduced by Apremilast. In the murine air pouch model, both Apremilast and methotrexate (MTX) significantly inhibit leukocyte infiltration, while Apremilast, but not MTX, significantly inhibits TNF-α release. The addition of MTX (1 mg/kg) to Apremilast (5 mg/kg) yields no more inhibition of leukocyte infiltration or TNF-α release than with Apremilast alone^[1].
Apremilast is a novel, oral PDE4 inhibitor that has been shown to regulate inflammatory mediators. After oral administration of Apremilast, a mean maximum plasma concentration (C_max) is found to be 67.00±14.87 ng/mL. The plasma concentration of Apremilast decreases rapidly and is eliminated from plasma with a terminal half-life of 0.92±0.46 h^[2]