Effect of hepatic or renal impairment on the pharmacokinetics of casopitant, a NK-1 receptor antagonist

• Published in: Investigational new drugs 2012-04, Vol.30 (2), p.662-671
• Main Authors: Bauman, John W., Antal, Joyce M., Adams, Laurel M., Johnson, Brendan M., Murray, Sharon C., Peng, Bin, Kirby, Lyndon C., Lebowitz, Peter F., Marbury, Thomas C., Swan, Suzanne, Gutierrez, Maria
• Format: Article
• Language: English
• Subjects: Acute coronary syndromes; Administration, Oral; Adult; Analysis of Variance; Angina pectoris; Antiemetics - administration & dosage; Antiemetics - adverse effects; Antiemetics - pharmacokinetics; Area Under Curve; Biotransformation; Body mass index; Cancer therapies; Cardiac arrhythmia; Chemotherapy; Classification; Clinical trials; Creatinine; Drug Administration Schedule; Drug dosages; Female; Gender; Heart failure; Humans; Kidney Diseases - blood; Kidney Diseases - metabolism; Kinases; Least-Squares Analysis; Liver diseases; Liver Diseases - blood; Liver Diseases - metabolism; Male; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Models, Biological; Nausea; Neurokinin-1 Receptor Antagonists; Oncology; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - pharmacokinetics; Piperidines - administration & dosage; Piperidines - adverse effects; Piperidines - pharmacokinetics; Protein Binding; Race; Severity of Illness Index; Side effects; Studies; United States; Vomiting
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-010-9604-2

Summary 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.