title: 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.affiliation: Drug Metabolism and Pharmacokinetics Department, Celgene, Summit, NJ, USA. mjhoffman@celgene.com
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
authors.forename: Dorota
authors.initials: D
authors.lastname: Cedzik
authors.forename: Lori
authors.initials: L
authors.lastname: Capone
authors.forename: Kei-Lai
authors.initials: KL
authors.lastname: Fong
authors.forename: Zheming
authors.initials: Z
authors.lastname: Gu
authors.forename: Dennis
authors.initials: D
authors.lastname: Heller
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: Oscar
authors.initials: O
authors.lastname: Laskin
authors.forename: Anfan
authors.initials: A
authors.lastname: Wu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002250:Carbon Radioisotopes; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011851:Radioactivity; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C505730:apremilast