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

Abstract

Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and 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 [(14)C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean C(max), AUC(0-∞) and t(max) 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.

Figures

Figure 1

Structure of apremilast, with the site of the 14C label indicated (*).

Figure 2

Cumulative elimination of radioactivity in urine and faeces after a single oral 20-mg dose of [14C]apremilast in male healthy subjects (ourine, o faeces, ? total). Values are mean ± standard deviation.

Figure 3

Concentration versus time curves for radioactivity in plasma (○), apremilast in plasma (•) and radioactivity in blood (▪) following a single oral 20-mg dose of [14C]apremilast in healthy male subjects. Values are mean ± standard deviation.

Figure 4

Concentration versus time curves for total radioactivity (TRA), apremilast, Mil, M12, M13, M14 and M16 in plasma following a single oral 20-mg dose of [14C]apremilast in healthy male subjects. Values are mean ± standard deviation.

Figure 5

Representative radiochromatograms of (A) 0-24-h pooled plasma, (B) 0-24-h pooled urine and (C) 0-48-h pooled faeces after a single oral 20-mg dose of [14C]apremilast in healthy male subjects.

Figure 6

Mass spectral fragmentation of apremilast.

Figure 7

Metabolic scheme of apremilast in humans. For hydrolysed phthalidomide ring products, only one of two possible forms is shown. [M5, O-desethyl apremilast, was not observed in this study and is a proposed intermediate metabolite] (GLU: glucuronic acid, * site of 14C label).