Apremilast 10 mg · Tablets

Apremilast is an oral small molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action is not well defined.

Absorption — OTEZLA when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of OTEZLA.

OTEZLA XR when taken orally is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~6 hours. OTEZLA XR 75 mg administered once daily demonstrates comparable PK exposure (steady-state AUC and Cmax) to OTEZLA 30 mg twice daily. When administered with a high-fat meal, OTEZLA XR tmax was delayed by 3 hours and Cmax and AUC were increased by ~28% compared to fasted conditions. Therefore, OTEZLA XR may be taken without regard to meals.

Distribution — Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L.

Metabolism — Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.

Elimination — The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radiolabeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.