Pharmacokinetics, metabolism and excretion of intravenous [^l4C]‐palonosetron in healthy human volunteers

Abstract

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.

Management of postoperative nausea and vomiting: focus on palonosetron

“…Total body clearance of palonosetron in healthy subjects is approximately 160 ml/h/kg, with renal clearance approximately 66.5 mL/h/kg. This slow elimination results in a long terminal half-life of approximately 40 hours, 116,117 which contrasts with previous 5-HT 3 antagonists such as ondansetron (3-5 hours) and granisetron (5-8 hours) (see Table 1). …”

“…The pharmacokinetic profile of palonosetron has been evaluated in healthy volunteers 116,117 and cancer patients.…”

“…119 The main metabolites, N-oxide-palonosetron, 6-(S)-hydroxy-palonosetron and small amounts of 6-keto-Noxo-palonosetron display less than 1% of palonosetron's activity at 5-HT 3 receptors. 117 Although a small study (n = 6) comparing poor against extensive metabolizers of CYP2D6 substrates found no difference in effi cacy, 90,119 palonosetron has not been studied in ultrarapid metabolizers so it is possible that in this genotype it has reduced effi cacy.…”

“…Following initial rapid distribution, iv palonosetron undergoes a slow elimination phase, primarily handled by the kidney, with 83% of a 10 μg/kg dose being recovered from the urine after 240 hours 117 and 40% of the administered dose excreted unchanged. Total body clearance of palonosetron in healthy subjects is approximately 160 ml/h/kg, with renal clearance approximately 66.5 mL/h/kg.…”

“…Palonosetron is moderately bound to plasma proteins (62%) 119 and despite its extensive distribution, little is sequestered in erythrocytes. 117 In keeping with most 5-HT 3 antagonists, the metabolism of palonosetron is primarily in the liver by the cytochrome P450 enzyme system, with CYP2D6 the predominant isoenzyme and CYP3A4 and CYP1A2 of secondary importance. 119 The main metabolites, N-oxide-palonosetron, 6-(S)-hydroxy-palonosetron and small amounts of 6-keto-Noxo-palonosetron display less than 1% of palonosetron's activity at 5-HT 3 receptors.…”