Pharmacokinetic and Safety Evaluation of Palonosetron, a 5‐Hydroxytryptamine‐3 Receptor Antagonist, in U.S. and Japanese Healthy Subjects

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.

Efficacy of palonosetron for preventing postoperative nausea and vomiting: a systematic review and meta-analysis

“…[13][14][15][16][17] Palonosetron may also have other advantages for perioperative care. For example, a recent study reported by Cho et al 34 found that palonosetron 0.075 mg iv administered before induction of anesthesia reduced injection pain associated with rocuronium administration; the NNT was 2.94.…”

“…Méthodes Nous avons effectué une recherche systématique dans les bases de données MEDLINE Ò , EMBASE TM , le Registre central Cochrane des essais cliniques contrô lés et Web of Science Ò pour identifier les essais randomisés contrô lés qui ont abordé la comparaison de l'efficacité antiémétique dans les 24 premières heures suivant une chirurgie, du palonosétron et de l'ondansétron administrés à titre prophylactique. Les principaux critères d'évaluation étaient le pourcentage de participants éprouvant des nausées postopératoires (NPO), des vomissements postopératoires (VPO) ou les deux, dans la période précoce (0-6 heures) ou tardive (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) Postoperative nausea and vomiting (PONV), the big ''little problem'', 1 is the most common postoperative medical problem. From the perspective of both patients and healthcare providers, prophylaxis of PONV is equally as important as postoperative analgesia.…”

“…13,14 In addition, Rojas et al [15][16][17] showed features that differentiate palonosetron from other 5-HT 3 RAs: allosteric binding and positive cooperativity with 5-HT 3 R, triggering of 5-HT 3 R internalization and prolonged inhibition of receptor function, and inhibition of substance P (a mediator of emesis)-mediated responses. [15][16][17] Due to these unique characteristics, palonosetron may be a promising agent that could achieve long-lasting efficacy in the prevention of PONV.…”

Efficacy of Single Parenteral Dose of Palonosetron Versus Dexamethasone for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Surgeries Under General Anaesthesia

“…The antiemetic ability of the medication is achieved through the inhibition of 5-HT3 receptors involving both medullary chemoreceptor zone and GI tract. 9 This inhibition of 5-HT3 receptors, thus represses the visceral afferent acceleration of the vomiting focus likely in a roundabout way at the level of the region postrema and in addition through direct restraint of serotonin activity inside the zone of postrema and the chemoreceptor trigger zone. 10 Alternate mechanism seems to basically responsible for emetogenic chemotherapy-induced nausea and vomiting, since comparable temporal relationship have not been documented between serotonin and emesis caused beyond first day after a dose and these agents are generally not sole responsible in preventing or alleviating the delayed effect.…”

Evaluation of Palonosetron versus Ondansetron in Preventing Postoperative Nausea and Vomiting

“…The 5-hydroxytryptamine-3 (5-HT3) receptor antagonists are popular drugs for PONV prophylaxis because of their similar efficacy to droperidol or dexamethasone and their favourable side-effect profile.2 Palonosetron is a new, potent, selective 5-HT3receptor antagonist with a strong receptorbinding affinity and a long elimination halflife and, therefore, a long duration of efficacy [10], [11] .…”