Population pharmacokinetics of palonosetron and model-based assessment of dosing strategies
Palonosetron is the most recent 5-hydroxytryptamine-3 receptor antagonist, and its fixed dose of 0.075 mg is indicated for the prevention of postoperative nausea and vomiting. This study aimed to examine whether fixed dosing is more appropriate than body size-based dosing through the development of a population pharmacokinetic model and model-based simulations.
Fifty-one adult patients undergoing general anesthesia received single intravenous palonosetron administrations 30 min before the end of surgery. Palonosetron concentrations were measured in blood samples collected at various timepoints within 48 h. A population pharmacokinetic analysis was performed by non-linear mixed-effects modeling, and the area under the curves (AUCs) for fixed dosing and body size-based dosing were simulated.
The pharmacokinetics of palonosetron were best described by the three-compartment model, and lean body weight (LBW) was the most significant covariate for all pharmacokinetic parameters. In a patient with LBW of 40 kg, typical clearance and central volume of distribution were 0.102 L/min and 6.98 L, respectively. In simulations, the overall interindividual variability in AUC (0, 48 h) of fixed dosing was not much higher than that of body size-based dosing. In subgroup analysis, the AUCs (0, 48 h) of fixed dosing were considerably lower in the high-weight subgroup and higher in the low-weight subgroup than the median-weight subgroup. In contrast, LBW-based dosing showed similar AUC distributions among the three subgroups.
LBW-based dosing might be suitable for high-weight patients to avoid possible underdosing. Nevertheless, the current fixed dosing of palonosetron is acceptable for adult patients with normal weight.
KeywordsPalonosetron Pharmacokinetics PONV
The study was registered with the Clinical Research Information Service, Republic of Korea (https://cris.nih.go.kr), prior to patient enrolment under registration number KCT0001254.
Compliance with ethical standards
Conflict of interest
No external funding and no competing interests declared.
- 1.Gan TJ, Diemunsch P, Habib AS, Kovac A, Kranke P, Meyer TA, Watcha M, Chung F, Angus S, Apfel CC, Bergese SD, Candiotti KA, Chan MT, Davis PJ, Hooper VD, Lagoo-Deenadayalan S, Myles P, Nezat G, Philip BK, Tramer MR, Society for Ambulatory Anesthesia. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118:85–113.CrossRefGoogle Scholar
- 2.Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N, Investigators I. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441–51.CrossRefGoogle Scholar
- 5.Guidance for Industry. Population pharmacokinetics: United States Food and Drug Administration; 1999. https://www.fda.gov/downloads/Guidance/UCM072137.pdf. Accessed 04/04/2018.
- 12.Aloxi (palonosetron HCl) injection prescribing information: Helsinn Healthcare SA; 2015. https://www.aloxi.com/docs/pdf/pi.pdf. Accessed 04/10/2018.
- 14.Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317:1098.Google Scholar
- 26.Kovac AL, Eberhart L, Kotarski J, Clerici G, Apfel C, Palonosetron 04-07 Study Group. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg. 2008;107:439–44.CrossRefGoogle Scholar
- 27.Candiotti KA, Kovac AL, Melson TI, Clerici G, Joo Gan T, Palonosetron 04-06 Study Group. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg. 2008;107:445–51.CrossRefGoogle Scholar
- 28.Muchatuta NA, Paech MJ. Management of postoperative nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag. 2009;5:21–34.Google Scholar
- 35.Bataille A, Letourneulx JF, Charmeau A, Lemedioni P, Leger P, Chazot T, Le Guen M, Diemunsch P, Fischler M, Liu N. Impact of a prophylactic combination of dexamethasone-ondansetron on postoperative nausea and vomiting in obese adult patients undergoing laparoscopic sleeve gastrectomy during closed-loop propofol-remifentanil anaesthesia: a randomised double-blind placebo-controlled study. Eur J Anaesthesiol. 2016;33:898–905.CrossRefGoogle Scholar
- 36.Mendes MN, Monteiro Rde S, Martins FA. Prophylaxis of postoperative nausea and vomiting in morbidly obese patients undergoing laparoscopic gastroplasties: a comparative study among three methods. Rev Bras Anestesiol. 2009;59:570–6.Google Scholar
- 38.White PF, Scuderi P. Prevention of postoperative nausea and vomiting (PONV): a dose-ranging study involving palonosetron, a potent 5-HT3 receptor antagonist. Anesthesiology. 2005;103:A703.Google Scholar