Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)-(GW679769)] is a novel neurokinin-1 receptor antagonist being developed for the prevention of chemotherapy-induced and postoperative nausea and vomiting. The disposition of [ 14 C]casopitant was determined in a single-sequence study in six healthy male subjects after single-dose 90-mg i.v. and 150-mg oral administration. Blood, urine, and feces were collected at frequent intervals after dosing. Plasma, urine, and fecal samples were analyzed by high-performance liquid chromatography/mass spectrometry coupled with off-line radiodetection for metabolite profiling. Moreover, urine was also analyzed with 1 H-NMR to further characterize metabolites. Plasma pharmacokinetic parameters for casopitant, a major metabolite (M13, coded as GSK525060), and total radioactivity were determined. Absorption of radioactivity after oral administration appeared to be nearly complete; elimination was principally via the feces both after oral and intravenous administration. Urinary elimination accounted for only <8% of total radioactivity. The main circulating metabolites were a hydroxylated derivative, M13 (coded as GSK525060), and, after oral administration, a deacetylated and oxidized metabolite, M12 (coded as GSK631832). In addition, many other metabolites were identified in plasma and excreta: the principal route of metabolism included multiple oxidations, loss of the N-acetyl group, modifications or loss of the piperazine group, and cleavage of the molecule. Casopitant was extensively metabolized, and only negligible amounts were excreted as unchanged compound. Some phase II metabolites were also observed, particularly in urine.Casopitant, also known as GW679769, is a novel, potent and selective orally available neurokinin-1 (NK-1) receptor antagonist, which has shown efficacy in the prevention of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (Arpornwirat et al., 2006;Chung et al., 2006;Rolski et al., 2006;Singla et al., 2006;Aziz et al., 2008;Grunberg et al., 2008;Herrstedt et al., 2008;Navari, 2008;Strausz et al., 2008). The site of action of NK-1 receptor antagonists for the prevention of emesis is believed to be the nucleus tractus solitarius, where vagal afferents from the gastrointestinal tract and inputs from the area postrema and other regions of the brain important in the control of emesis converge. For the prevention of nausea and vomiting, casopitant has been administered as a single dose or as part of an acute 3-day dosing regimen. Casopitant is administered in combination with a 5-HT3 receptor antagonist, such as ondansetron, and for the prevention of CINV, dexamethasone is also coadministered. Clinical studies have evaluated the safety and effectiveness of a single 50-mg oral dose of casopitant for postoperative nausea and vomiting and single (150 mg oral) or 3-day (90 mg i.v. or 150 mg oral on day 1, followed b...

species: the maximum plasma concentration of radioactivity was generally observed 0.5 to 2 h after a single oral dose. In dog and female rat, as observed for humans, the principal circulating radiolabeled components were unchanged casopitant and its hydroxylated derivative M13. In rats, there was an evident sex-related difference in the rate of elimination of drug-related material with elimination being more rapid in males than in females. In dogs and mice, no notable sex differences were observed in the pattern of excretion. The elimination of drug-related radioactivity was largely by metabolism, with metabolites excreted primarily in the feces. The predominant route of metabolism was the oxidation of the parent molecule, observed together with loss of the Nacetyl group, N-demethylation, and modification of piperazine with consequent opening and cleavage of the ring, giving a complex pattern of metabolites. Conjugation of some of those oxidized products with glucuronic acid was observed. Urinary excretion in all three species was a minor route of elimination, accounting for between 2 and 7% of the dose, with unchanged parent drug never quantifiable.

were the major components quantified. After a 26-week repeat dose study in dog, casopitant and M13 were the major circulating components, whereas in myocardium, M200 and M134 were the major ones and their levels increased over time, reaching considerable concentrations (millimolar magnitude). After a washout period, all circulating derivatives decreased to undetectable levels, whereas M200 was still the major component in myocardium.Overall DRM in plasma did not correlate with the respective concentrations in tissues.