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...

These experiments may sometimes still be relevant to explain toxicological findings or for other special purposes but should not be considered required pieces of the registration dossiers. An appropriate investigation of samples coming from safety evaluation and human Phase I studies and the knowledge generated during the lead optimization phase provide, in most instances, all the DMPK information needed to take decisions in the drug development process.

The authors propose that clinical ex vivo protein-binding studies should be performed on highly bound compounds (a definition of highly bound is suggested as > 95%). They also propose that in vitro studies, to measure the free drug, should be performed in whole blood, rather than in plasma, particularly if binding to proteins or blood cells is nonlinear.

N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [14 C]SB-649868 was determined in eight healthy male subjects using an open-label study design after a single oral dose of 30 mg. Blood, urine, and feces were collected at frequent intervals after dosing, and samples were analyzed by high-performance liquid chromatography-mass spectrometry coupled with off-line radiodetection for metabolite profiling and characterization. NMR spectroscopy was also used to further characterize certain metabolites. Elimination of drugrelated material was almost complete over a 9-day period, occurring principally via the feces (79%), whereas urinary excretion accounted only for 12% of total radioactivity. Mean apparent halflife (t 1/2 ) of plasma radioactivity was notably longer (

The authors advocate directing more attention and efforts toward investigating tissue distribution: this approach might reduce late stage attrition. When unexpected tissue toxicity is found, measuring drug concentrations in the target tissue and characterising and measuring tissue metabolites could bring relevant information for interpreting the adverse finding. Evidence of slow accumulation of a long lasting metabolite in a tissue should be considered as an alert: this evidence can be obtained during short-term toxicity studies.