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.

• Authors: Matthew Hoffmann, Gondi Kumar, Peter Schafer, Dorota Cedzik, Lori Capone, Kei-Lai Fong, Zheming Gu, Dennis Heller, Hao Feng, Sekhar Surapaneni, Oscar Laskin, Anfan Wu
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 41 Issue 12 Pg. 1063-75 (Dec 2011) ISSN: 1366-5928 [Electronic] England
• PMID: 21859393 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbon Radioisotopes
• Phosphodiesterase 4 Inhibitors
• Tumor Necrosis Factor-alpha
• Thalidomide
• Cyclic Nucleotide Phosphodiesterases, Type 4
• apremilast

Topics

• Administration, Oral
• Adult
• Carbon Radioisotopes
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Humans
• Male
• Mass Spectrometry
• Middle Aged
• Phosphodiesterase 4 Inhibitors (administration & dosage, chemistry, metabolism, pharmacokinetics)
• Radioactivity
• Thalidomide (administration & dosage, analogs & derivatives, chemistry, metabolism, pharmacokinetics)
• Time Factors
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
• Young Adult