Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects.
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Stoltz R, Cyong JC, Shah A, Parisi S
Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects.
J Clin Pharmacol. 2004 May;44(5):520-31.
- PubMed ID
- 15102873 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Palonosetron 5-hydroxytryptamine receptor 3A Protein Humans YesAntagonistDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Palonosetron Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails Palonosetron Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Palonosetron Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails