Pharmacokinetics and Brain Penetration of Casopitant, a Potent and Selective Neurokinin-1 Receptor Antagonist, in the Ferret

Abstract

ABSTRACT:The pharmacokinetics and brain penetration of the novel neurokinin (NK) The tachykinins are a family of peptide neurotransmitters that mediate the release of intracellular calcium by binding to a group of transmembrane receptors called neurokinins (NK). NK-1 receptor antagonists are believed to confer antiemetic activity by suppressing the activity of the nucleus tractus solitarius, which is the point at which the vagal afferents from the gastrointestinal tract converge with inputs from the area postrema and other regions of the brain believed to be important in the control and initiation of emesis. Casopitant (GW679769) is a potent and selective NK-1 receptor antagonist. It is currently in Phase III clinical development for the treatment of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. Previous animal and human studies have shown that casopitant has antiemetic activity in vivo (Arpornwirat et al., 2006;King, 2006;Rolski et al., 2006).-The ferret is known to respond to the full spectrum of agents recognized to induce emesis in humans (King, 1990). The cisplatininduced acute and delayed emesis models in the ferret have been used extensively to identify the antiemetic potential of novel drug therapies, including casopitant. In these models, casopitant has shown a prolonged effect in the attenuation of cisplatin-induced emesis. This suggests that casopitant may be helpful in treating human patients undergoing chemotherapy who experience persistent nausea and vomiting for several days after drug treatment. Brain penetration and subsequent receptor occupancy are expected to be important factors that influence the onset and duration of the pharmacologic effects of casopitant. It is not known whether the major metabolites of casopitant have NK-1 antagonist activity or if the prolonged pharmacodynamic effects of casopitant observed in the ferret are caused by casopitant itself, one of its metabolites, or a combination. A better understanding of the pharmacokinetics and drug metabolism in the ferret is essential to elucidating the pharmacodynamic contribution of casopitant and its circulating metabolite(s) to the therapeutic effects observed in ferret emesis models.Selective NK-1 receptor antagonists provide incremental improve- Article, publication date, and citation information can be found at

Disposition and Metabolism of Radiolabeled Casopitant in Humans

“…Their affinity to NK-1 receptors was determined in vitro and was similar to casopitant (data not presented). However, because these metabolites have reduced brain penetration when compared with casopitant in animals (Minthorn et al, 2008), and lower clinical plasma exposure than casopitant (Tables 2 and 3), their contribution to the overall pharmacological activity of casopitant is expected to be small.…”

“…The elimination half-life was 1.8 h in rats and 4.5 h in dogs. Metabolism and brain penetration have also been studied in the ferret (Minthorn et al, 2008). …”

Casopitant: a novel NK1-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting

“…Casopitant in chemotherapy-induced nausea and vomiting Dovepress submit your manuscript | www.dovepress.com Dovepress 76%, 19%, and 3% of the radioactivity, respectively; suggesting that the pharmacologic activity of casopitant in the ferret is largely attributable to the parent compound. 26 An in vitro receptor binding affinity study describes, that casopitant possesses a high affinity for brain NK 1 receptors in the ferret. 26 Because casopitant is intended to be administered in combination with a 5-HT 3 -receptor antagonist and because therapeutic synergy has been observed with this combination in the ferret, a drug interaction study was conducted.…”

“…26 An in vitro receptor binding affinity study describes, that casopitant possesses a high affinity for brain NK 1 receptors in the ferret. 26 Because casopitant is intended to be administered in combination with a 5-HT 3 -receptor antagonist and because therapeutic synergy has been observed with this combination in the ferret, a drug interaction study was conducted. 28 Following co-administration of ondansetron and casopitant in ferrets, no alteration of disposition of either agent was seen.…”

“…Casopitant is a piperazine derivative [1-piperidinecarboxamide, 4-(4-acetyl-1-piperazinyl)-N-((1R)-1(3,5-bis(trifluorometh yl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl-N-methyl-(2R,4S)-; GW679769] ( Figure 1). 26 In a ferret-model of cisplatin-induced emesis, GW679769 (casopitant) inhibited retching and vomiting and reduced nausea-like behaviours in a dose-dependent manner. [27][28][29] Several clinical trials have assessed safety, potential interactions and pharmacokinetic properties of casopitant; however many data is available in abstract form only.…”