Abstract C132: Effect of hepatic or renal impairment on the pharmacokinetics of casopitant
Authors: Bauman John W. , Antal Joyce M. , Adams Laurel M. , Johnson Brendan M. , Murray Sharon C. , Kirby Lyndon C. , Lebowitz Peter F. , Peng Bin , Marbury Thomas C. , Swan Suzanne , Gutierrez Maria 
Published: June 2012

Introduction: The pharmacokinetics and safety of casopitant, a neurokinin-1 receptor antagonist being developed for the prevention of chemotherapy-induced and post-operative nausea and vomiting, were evaluated in subjects with mild (Child-Pugh score of 5–6) and moderate (Child-Pugh score of 7–9) hepatic impairment; mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–49 mL/min) renal impairment; and subjects with normal hepatic and renal function.

Experimental Design: Twenty-six subjects were enrolled in the hepatic impairment study (9 mild, 9 moderate and 8 normal subjects) and 18 subjects in the renal impairment study (6 mild, 6 moderate and 6 normal subjects). Subjects with severe hepatic or renal impairment were excluded. All subjects received a once-daily dose of 100 mg oral casopitant for 5 days. Pharmacokinetics and plasma protein binding of casopitant and its major metabolite, GSK525060, were determined on Days 1 and 5. Safety was continuously assessed.

Results: Subjects with mild or moderate hepatic impairment had an increase in casopitant AUC of 11% and 24%, respectively, on Day 1 compared with normal subjects; a similar increase was observed on Day 5. Casopitant Cmax was variable, but similar across all subjects. GSK525060 AUC was not significantly different between normal subjects and subjects with mild hepatic impairment; however, AUC was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment. The percent bound of casopitant and GSK525060 was similar in all subjects. Casopitant AUC increased 34% and 22% in subjects with mild or moderate renal impairment on Day 1, respectively, and 28% and 11% on Day 5, respectively, when compared with normal subjects. GSK525060 AUC 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 impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Cmax and half-life in renal impaired subjects were similar to normal subjects. The plasma protein-binding of casopitant and GSK525060 was similar in all subjects. Casopitant was well tolerated, with no significant difference in the type or frequency of adverse events (AEs) noted between subjects with mild, moderate or no hepatic or renal impairment. Somnolence, flatulence and nausea were the most frequently reported AEs in the hepatic impairment study; whereas constipation and dyspepsia were the most frequently reported events in the renal impairment study. No AEs were reported in subjects with mild renal impairment.

Conclusion: 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 on the pharmacokinetics and safety of casopitant was not evaluated.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C132.