Palonosetron (Aloxi, Onicit) is a selective 5-HT(3) receptor antagonist recently approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. This study was performed to determine the pharmacokinetics and assess the safety and tolerability of intravenous (IV) palonosetron in healthy U.S. and Japanese subjects. Subjects were administered a single IV dose of palonosetron, ranging from 0.3 to 90 microg/kg in either of two randomized, double-blind, placebo-controlled, ascending-dose studies (n = 80 and n = 32, respectively). Serial blood samples were obtained in both studies to evaluate the pharmacokinetics of palonosetron and its N-oxide metabolite, M9. Intravenous palonosetron was well tolerated across a wide range of doses in both studies. The incidence and severity of adverse events (AEs) were similar between subjects receiving palonosetron and those receiving placebo, with no dose-dependent incidences. The most frequently reported AEs were headache, transient elevation of liver enzymes, and constipation. Systemic exposure (AUC and C(max)) for palonosetron generally increased with increasing dose. Mean total body clearance, elimination half-life, and apparent volume of distribution ranged from 1.11 to 3.90 mL/min/kg, 33.7 to 54.1 hours, and 3.85 to 12.6 L/kg, respectively, in U.S. subjects and from 2.58 to 3.50 mL/min/kg, 30.8 to 36.8 hours, and 6.96 to 9.85 L/kg, respectively, in Japanese subjects. The pharmacokinetics of palonosetron appeared to be independent of dose, with no dose adjustment required in Japanese subjects. The plasma concentration profile of palonosetron, as represented by a half-life of approximately 40 hours, may provide a clinical advantage over other 5-HT(3) antagonists.
Palonosetron (Aloxi(R), Onicit(R)) is a potent, single stereoisomeric 5-HT(3) receptor antagonist developed to prevent chemotherapy-induced nausea and vomiting. The pharmacokinetics and metabolic disposition of a single intravenous [(14)C]-palonosetron (10 microg/kg, 0.8 microCi/kg) bolus dose were evaluated in six healthy volunteers (three males, three females) using serial blood, plasma, urine and fecal samples obtained over 10 days. The safety, tolerability and cardiac effects were assessed. Radiolabeled metabolic characterization revealed that unchanged palonosetron accounted for 71.9% of the total radioactivity in plasma over 96 h, with an extensive distribution volume (8.34 l/kg) and mean plasma elimination half-life of 37 h. Approximately 83% of the dose was recovered in urine ( approximately 40% as unchanged drug, with 50% metabolized; M9 and M4 were the major metabolites) and 3.4% in feces. Hydrolysis of urine samples suggests that the metabolites are not beta-glucuronide or sulfate conjugates of the parent drug or metabolites. The blood to plasma concentration ratio of the total radioactivity was 1.2, on average, indicating little selective partitioning in erythrocytes. Palonosetron was generally well tolerated; headache was the most frequently reported adverse event. Electrocardiograms and 72 h Holter monitoring revealed no clinically significant changes. Palonosetron circulates in plasma mainly as the parent drug. Renal elimination is the primary excretion route, with parent drug and metabolites M9 and M4 accounting for the majority of palonosetron disposition. These results indicate that both renal and hepatic routes are involved in the elimination of palonosetron from the body.
Obese subjects candidate to bariatric surgery have a high risk of disruption of EGJ morphology. In particular, obese patients with hiatal hernia often refer pre-operative presence of GERD symptoms. Testing obese patients with HRM before undergoing bariatric surgery, especially for restrictive procedures, can be useful for assessing presence of hiatal hernia.
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