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Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subjects with normal organ function to evaluate the pharmacokinetics of casopitant and to assess its safety in these populations. A total of 26 subjects were enrolled in the hepatic impairment study and 18 subjects in the renal impairment study. All subjects received oral casopitant 100 mg once-daily for 5 days. Casopitant area under the concentration-time curve (AUC) increased 11% and 24% in subjects with mild or moderate hepatic impairment, respectively, on Day 1, compared with subjects with normal hepatic function; a similar increase was observed on Day 5. The AUC of the active major metabolite, GSK525060, was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment, but not altered by mild hepatic impairment. Casopitant AUC increased 34% and 22% on Day 1 in subjects with mild or moderate renal impairment, respectively, and 28% and 11% on Day 5, respectively, compared with subjects with normal renal function. GSK525060 AUC was increased 17% and 24% on Days 1 and 5, respectively, in subjects with mild renal impairment; but did not significantly change in subjects with moderate renal impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Plasma protein binding of casopitant and GSK525060 was similar in all subjects. The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment was not evaluated.

Hypothesis: Postoperative nausea and vomiting (PONV) are associated with a variety of complications. Neurokinin subtype 1 receptor antagonists have antiemetic activity in the postoperative setting, and the neurokinin subtype 1 receptor antagonist casopitant mesylate (GW679769) was well tolerated and effective at reducing the incidence of PONV in phase 1 and phase 2 trials., Design: A multicenter, randomized, double-blind, parallel-group, phase 3 analysis was designed to evaluate the safety and efficacy of casopitant in combination with a single intravenous dose of the serotonin subtype 3 receptor antagonist ondansetron hydrochloride for the prevention of PONV in the perioperative setting., Setting: Forty-three centers in 11 countries., Patients: We studied 484 women at high risk for developing PONV scheduled to undergo operations associated with high emetogenic risk., Interventions: The women were randomized to receive a single dose of intravenous ondansetron, 4 mg, or oral casopitant, 50 mg, in combination with intravenous ondansetron, 4 mg., Main Outcome Measures: The primary end point was the proportion of patients who achieved a complete response, defined as no vomiting, retching, or rescue therapy. Patients received a balanced anesthetic regimen., Results: Between March 20 and August 31, 2006, 484 patients were enrolled in the study. Patients in the casopitant plus ondansetron group had a 68.7% rate of complete response during the first 24 hours after surgery compared with 58.7% in the ondansetron-only group (P = .03). The difference between groups in complete response from 24 to 48 hours (63.4% with ondansetron only vs 70.0% with ondansetron plus casopitant) was not significant. No vomiting for 0 to 24 hours was observed in 89.7% of the casopitant plus ondansetron group compared with 74.9% of the ondansetron-only group (P < .001). Oral casopitant administered in combination with ondansetron was well tolerated., Conclusions: The results of this pivotal phase 3 study demonstrate that the combination of casopitant and ondansetron was superior to ondansetron only in patients at high risk for PONV. Trial Registration clinicaltrials.gov Identifier: NCT00326248.

Chemotherapy-induced nausea and vomiting (CINV) is a serious adverse effect of chemotherapy that limits patients' physical, mental, and functional capabilities and may cause a delay or cessation of treatment. Antiemetic therapy can reduce the incidence of CINV. Research, using data from visits by patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC), identified that antiemetics were prescribed for 86% (in 2007) and 82% (in 2008) of patients receiving MEC or HEC. For these visits, 5-hydroxytryptamine-3 receptor antagonists were prescribed in at least 97% of visits for both years, whereas neurokinin-1 (NK-1) receptor antagonists were prescribed at a rate of 10% and 11%, respectively. Studies show that nurses and physicians underestimate the incidence of CINV after HEC and MEC. Oncology nurses often critically influence patients' selection of CINV therapy and can play a significant role in increasing awareness about the benefits of adding an NK-1 receptor antagonist to standard prophylactic regimens for acute and delayed CINV.