Advertisement

Population pharmacokinetics of palonosetron and model-based assessment of dosing strategies

  • Seongheon Lee
  • Injae Kim
  • Taehee Pyeon
  • Sooeun Lee
  • Jia Song
  • Jeeyun Rhee
  • Seongwook JeongEmail author
Original Article

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Palonosetron Pharmacokinetics PONV 

Notes

Acknowledgements

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.

References

  1. 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. 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
  3. 3.
    Habib AS, White WD, Eubanks S, Pappas TN, Gan TJ. A randomized comparison of a multimodal management strategy versus combination antiemetics for the prevention of postoperative nausea and vomiting. Anesth Analg. 2004;99:77–81.CrossRefGoogle Scholar
  4. 4.
    Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.CrossRefGoogle Scholar
  5. 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.
  6. 6.
    Jain D, Jain K, Bala I, Gandhi K. Evaluation of weight-adjusted doses of palonosetron for prevention of postoperative nausea and vomiting in day care laparoscopic gynaecological surgery: a dose ranging, randomised controlled trial. Eur J Anaesthesiol. 2016;33:104–9.CrossRefGoogle Scholar
  7. 7.
    Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacomet Syst Pharmacol. 2012;1:e6.CrossRefGoogle Scholar
  8. 8.
    Stoltz R, Parisi S, Shah A, Macciocchi A. Pharmacokinetics, metabolism and excretion of intravenous [l4C]-palonosetron in healthy human volunteers. Biopharm Drug Dispos. 2004;25:329–37.CrossRefGoogle Scholar
  9. 9.
    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;44:520–31.CrossRefGoogle Scholar
  10. 10.
    Hunt TL, Gallagher SC, Cullen MT Jr, Shah AK. Evaluation of safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron in healthy subjects. J Clin Pharmacol. 2005;45:589–96.CrossRefGoogle Scholar
  11. 11.
    Eisenberg P. Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol. 2004;15:330–7.CrossRefGoogle Scholar
  12. 12.
    Aloxi (palonosetron HCl) injection prescribing information: Helsinn Healthcare SA; 2015. https://www.aloxi.com/docs/pdf/pi.pdf. Accessed 04/10/2018.
  13. 13.
    Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44:1051–65.CrossRefGoogle Scholar
  14. 14.
    Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317:1098.Google Scholar
  15. 15.
    Pai MP, Paloucek FP. The origin of the "ideal" body weight equations. Ann Pharmacother. 2000;34:1066–9.CrossRefGoogle Scholar
  16. 16.
    Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol. 1983;24:643–7.CrossRefGoogle Scholar
  17. 17.
    Wahlby U, Jonsson EN, Karlsson MO. Assessment of actual significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn. 2001;28:231–52.CrossRefGoogle Scholar
  18. 18.
    Ette EI, Ludden TM. Population pharmacokinetic modeling: the importance of informative graphics. Pharm Res. 1995;12:1845–55.CrossRefGoogle Scholar
  19. 19.
    Yafune A, Ishiguro M. Bootstrap approach for constructing confidence intervals for population pharmacokinetic parameters. I: a use of bootstrap standard error. Stat Med. 1999;18:581–99.CrossRefGoogle Scholar
  20. 20.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–51.CrossRefGoogle Scholar
  21. 21.
    Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004;75:85–94.CrossRefGoogle Scholar
  22. 22.
    Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development—part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacomet Syst Pharmacol. 2013;2:e38.CrossRefGoogle Scholar
  23. 23.
    Ette EI, Williams PJ, Kim YH, Lane JR, Liu MJ, Capparelli EV. Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol. 2003;43:610–23.CrossRefGoogle Scholar
  24. 24.
    Xiong C, Liu G, Ma R, Xue J, Wu A. Efficacy of palonosetron for preventing postoperative nausea and vomiting: a systematic review and meta-analysis. Can J Anaesth. 2015;62:1268–78.CrossRefGoogle Scholar
  25. 25.
    Singh PM, Borle A, Gouda D, Makkar JK, Arora MK, Trikha A, Sinha A, Goudra B. Efficacy of palonosetron in postoperative nausea and vomiting (PONV)—a meta-analysis. J Clin Anesth. 2016;34:459–82.CrossRefGoogle Scholar
  26. 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. 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. 28.
    Muchatuta NA, Paech MJ. Management of postoperative nausea and vomiting: focus on palonosetron. Ther Clin Risk Manag. 2009;5:21–34.Google Scholar
  29. 29.
    Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet. 2000;39:215–31.CrossRefGoogle Scholar
  30. 30.
    Morgan DJ, Bray KM. Lean body mass as a predictor of drug dosage. Implications for drug therapy. Clin Pharmacokinet. 1994;26:292–307.CrossRefGoogle Scholar
  31. 31.
    Navari RM. Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy. Cancer Manag Res. 2009;1:167–76.CrossRefGoogle Scholar
  32. 32.
    Yang LP, Scott LJ. Palonosetron: in the prevention of nausea and vomiting. Drugs. 2009;69:2257–78.CrossRefGoogle Scholar
  33. 33.
    Morganroth J, Flaharty KK, Parisi S, Moresino C. Effect of single doses of IV palonosetron, up to 2.25 mg, on the QTc interval duration: a double-blind, randomized, parallel group study in healthy volunteers. Support Care Cancer. 2016;24:621–7.CrossRefGoogle Scholar
  34. 34.
    Kim HJ, Lee HC, Jung YS, Lee J, Min JJ, Hong DM, Choi EK, Oh S, Jeon Y. Effect of palonosetron on the QTc interval in patients undergoing sevoflurane anaesthesia. Br J Anaesth. 2014;112:460–8.CrossRefGoogle Scholar
  35. 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. 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
  37. 37.
    de Alwis DP, Aarons L, Palmer JL. Population pharmacokinetics of ondansetron: a covariate analysis. Br J Clin Pharmacol. 1998;46:117–25.CrossRefGoogle Scholar
  38. 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

Copyright information

© Japanese Society of Anesthesiologists 2019

Authors and Affiliations

  1. 1.Department of Anesthesiology and Pain MedicineChonnam National University Medical SchoolGwangjuSouth Korea
  2. 2.Department of Molecular MedicineChonnam National University Medical SchoolGwangjuSouth Korea

Personalised recommendations