Disposition, metabolism and mass balance of [¹⁴C]apremilast following oral administration

Abstract

Apremilast is a novel, orally available small molecule that specifically inhibits PDE4and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis.The pharmacokinetics and disposition of [14C]apremilastwas investigated following a single oral dose (20 mg, 100 uCi) to healthy male subjects.Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean Cmax, AUC0 and tmax values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and <7% of the excreted radioactivity.The predominant metabolite was O-desmethyl apremilast glucuronide, representing 39% of plasma radioactivity and 34% of excreted radioactivity. The only other radioactive components that represented >4%of the excreted radioactivity were O-demethylated apremilast and its hydrolysis product. Additional minor circulating and excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-enzymatic hydrolysis and excretion of unchanged drug were involved to a lesser extent.

Apremilast

“…1,2,8 Apremilast is a novel, orally available small molecule that inhibits the activity of PDE4, subsequently inhibiting the production of TNF-alpha, IL-2, IL-8, IL-12, IL-23, CXCL9, CXCL10, CCL4, interferongamma, and leukotriene B4 and increasing the production of IL-10. [1][2][3][4][5][8][9][10] The specifi c mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients is not well defi ned. 1 Apremilast also suppresses arthritis in rodents and reduces the severity of psoriasiform features in mice with psoriatic xenografts.…”

“…9 Following oral administration of radiolabeled apremilast, about 58% and 39% of the radioactivity and about 3% and 7% of unchanged radioactive apremilast is recovered in urine and feces, respectively. 1,9 The pharmacokinetics of apremilast are not affected by moderate or severe hepatic impairment. In patients with severe renal impairment given a single dose of apremilast 30 mg, the area under the curve (AUC) and C max of apremilast increased by approximately 88% and 42%, respectively.…”

“…3,6,11 In healthy patients, apremilast plasma clearance is about 10 L/h, and the terminal elimination halflife is 6 to 9 hours. 1,7,9,12 The half-life of apremilast metabolites is 11 to 16 hours. 9 Following oral administration of radiolabeled apremilast, about 58% and 39% of the radioactivity and about 3% and 7% of unchanged radioactive apremilast is recovered in urine and feces, respectively.…”

“…1,7,9,12 The half-life of apremilast metabolites is 11 to 16 hours. 9 Following oral administration of radiolabeled apremilast, about 58% and 39% of the radioactivity and about 3% and 7% of unchanged radioactive apremilast is recovered in urine and feces, respectively. 1,9 The pharmacokinetics of apremilast are not affected by moderate or severe hepatic impairment.…”

Apremilast: A Review in Psoriasis and Psoriatic Arthritis

“…Apremilast undergoes extensive metabolism via multiple pathways; these include oxidative metabolism by cytochrome P450 (CYP) enzymes (primarily CYP3A4, and to a lesser extent CYP1A2 and CYP2A6), with subsequent glucuronidation and non-CYP-driven hydrolysis [8,17]. Up to 23 metabolites have been identified in humans [8], although these are unlikely to contribute appreciably to apremilast pharmacological activity as they generally cause considerably ([50-fold) less PDE4 and TNF-a inhibition or are present in the circulation at concentrations \2 % of the parent drug [17].…”