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Population pharmacokinetics of ramosetron

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Abstract

Ramosetron is a selective serotonergic 5-hydroxy-tryptamine receptor 3 antagonist that is used to prevent and treat postoperative nausea and vomiting. This study aimed to characterize the population pharmacokinetics of ramosetron in patients undergoing surgery with general anesthesia. Patients aged 19–80 years received a single intravenous bolus of ramosetron (0.3, 0.45, or 0.6 mg) 30 min before the end of surgery. Blood samples were collected, and plasma concentrations of ramosetron were measured by high performance liquid chromatography-tandem mass spectrometry. Pooled data from 50 patients and 479 pharmacokinetic samples were used for population pharmacokinetic analysis using the nonlinear mixed effect modeling program (NONMEM®). The pharmacokinetics of ramosetron was best described by a three-compartment mammillary model with first-order elimination. Based on allometric principles, body weight was incorporated in the base model, along with fixed allometric exponents. The typical value of clearance was 0.19 L/h in a 60-kg subject, and it decreased approximately 3 % for every year of age, starting at age of 57. The bootstrap method and visual predictive check showed that the final pharmacokinetic model was appropriate. A population pharmacokinetic model of ramosetron was constructed in adult surgical patients, providing a foundation for further defining the relationship between ramosetron dose and postoperative nausea and vomiting.

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References

  1. Watcha MF, White PF (1992) Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology 77(1):162–184

    Article  PubMed  CAS  Google Scholar 

  2. Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N (1999) A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 91(3):693–700

    Article  PubMed  CAS  Google Scholar 

  3. Sinclair DR, Chung F, Mezei G (1999) Can postoperative nausea and vomiting be predicted? Anesthesiology 91(1):109–118

    Article  PubMed  CAS  Google Scholar 

  4. American Society of Health-System Pharmacists (1999) ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery (1999). Am J Health Syst Pharm 56(8):729–764

    Google Scholar 

  5. 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 (2014) Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg 118(1):85–113. doi:10.1213/ANE.0000000000000002

    Article  PubMed  Google Scholar 

  6. Tramer MR, Reynolds DJ, Moore RA, McQuay HJ (1997) Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Anesthesiology 87(6):1277–1289

    Article  PubMed  CAS  Google Scholar 

  7. Golembiewski J, Tokumaru S (2006) Pharmacological prophylaxis and management of adult postoperative/postdischarge nausea and vomiting. J Perianesth Nurs 21(6):385–397. doi:10.1016/j.jopan.2006.09.004

    Article  PubMed  Google Scholar 

  8. Le TP, Gan TJ (2010) Update on the management of postoperative nausea and vomiting and postdischarge nausea and vomiting in ambulatory surgery. Anesthesiol Clin 28(2):225–249. doi:10.1016/j.anclin.2010.02.003

    Article  PubMed  Google Scholar 

  9. Kranke P, Eberhart LH, Apfel CC, Broscheit J, Geldner G, Roewer N (2002) Tropisetron for prevention of postoperative nausea and vomiting: a quantitative systematic review. Der Anaesthesist 51(10):805–814. doi:10.1007/s00101-002-0373-y

    Article  PubMed  CAS  Google Scholar 

  10. Birmingham SD, Mecklenburg BW, Lujan E, Dacanay RG, Boyle PK, Green R (2006) Dolasetron versus ondansetron as single-agent prophylaxis for patients at increased risk for postoperative nausea and vomiting: a prospective, double-blind, randomized trial. Mil Med 171(9):913–916

    Article  PubMed  Google Scholar 

  11. Ku CM, Ong BC (2003) Postoperative nausea and vomiting: a review of current literature. Singapore Med J 44(7):366–374

    PubMed  CAS  Google Scholar 

  12. Koch KM, Palmer JL, Noordin N, Tomlinson JJ, Baidoo C (2002) Sex and age differences in the pharmacokinetics of alosetron. Br J Clin Pharmacol 53(3):238–242

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Rabasseda X (2002) Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting. Drugs Today 38(2):75–89

    Article  PubMed  CAS  Google Scholar 

  14. Kranke P, Schuster F, Eberhart LH (2007) Recent advances, trends and economic considerations in the risk assessment, prevention and treatment of postoperative nausea and vomiting. Expert Opin Pharmacother 8(18):3217–3235. doi:10.1517/14656566.8.18.3217

    Article  PubMed  CAS  Google Scholar 

  15. Kim WO, Koo BN, Kim YK, Kil HK (2011) Ramosetron for the prevention of postoperative nausea and vomiting (PONV): a meta-analysis. Korean J Anesthesiol 61(5):405–412. doi:10.4097/kjae.2011.61.5.405

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Kadokura T, den Adel M, Krauwinkel WJ, Takeshige T, Nishida A (2008) The effect of fluvoxamine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects. Eur J Clin Pharmacol 64(7):691–695. doi:10.1007/s00228-008-0466-x

    Article  PubMed  CAS  Google Scholar 

  17. Kovac AL (2006) Prophylaxis of postoperative nausea and vomiting: controversies in the use of serotonin 5-hydroxytryptamine subtype 3 receptor antagonists. J Clin Anesth 18(4):304–318. doi:10.1016/j.jclinane.2005.06.012

    Article  PubMed  CAS  Google Scholar 

  18. Ho KY, Gan TJ (2006) Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol 19(6):606–611. doi:10.1097/01.aco.0000247340.61815.38

    Article  PubMed  Google Scholar 

  19. Cox EH, Veyrat-Follet C, Beal SL, Fuseau E, Kenkare S, Sheiner LB (1999) A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron. J Pharmacokinet Biopharm 27(6):625–644

    Article  PubMed  CAS  Google Scholar 

  20. de Alwis DP, Aarons L, Palmer JL (1998) Population pharmacokinetics of ondansetron: a covariate analysis. Br J Clin Pharmacol 46(2):117–125

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mondick JT, Johnson BM, Haberer LJ, Sale ME, Adamson PC, Cote CJ, Croop JM, Russo MW, Barrett JS, Hoke JF (2010) Population pharmacokinetics of intravenous ondansetron in oncology and surgical patients aged 1-48 months. Eur J Clin Pharmacol 66(1):77–86. doi:10.1007/s00228-009-0730-8

    Article  PubMed  CAS  Google Scholar 

  22. Mihara T, Tojo K, Uchimoto K, Morita S, Goto T (2013) Reevaluation of the effectiveness of ramosetron for preventing postoperative nausea and vomiting: a systematic review and meta-analysis. Anesth Analg 117(2):329–339. doi:10.1213/ANE.0b013e31829847a1

    Article  PubMed  CAS  Google Scholar 

  23. Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28(5):481–504

    Article  PubMed  CAS  Google Scholar 

  24. Pai MP, Paloucek FP (2000) The origin of the “ideal” body weight equations. Ann Pharmacother 34(9):1066–1069

    Article  PubMed  CAS  Google Scholar 

  25. Bouillon T, Shafer SL (1998) Does size matter? Anesthesiology 89(3):557–560

    Article  PubMed  CAS  Google Scholar 

  26. Karlsson MO, Savic RM (2007) Diagnosing model diagnostics. Clin Pharmacol Ther 82(1):17–20. doi:10.1038/sj.clpt.6100241

    Article  PubMed  CAS  Google Scholar 

  27. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO (2011) Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J 13(2):143–151. doi:10.1208/s12248-011-9255-z

    Article  PubMed  PubMed Central  Google Scholar 

  28. Comets E, Brendel K, Mentre F (2008) Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed 90(2):154–166. doi:10.1016/j.cmpb.2007.12.002

    Article  PubMed  Google Scholar 

  29. Jonsson EN, Karlsson MO (1999) Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58(1):51–64

    Article  PubMed  CAS  Google Scholar 

  30. Lindbom L, Ribbing J, Jonsson EN (2004) Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Programs Biomed 75(2):85–94. doi:10.1016/j.cmpb.2003.11.003

    Article  PubMed  Google Scholar 

  31. Yafune A, Ishiguro M (1999) Bootstrap approach for constructing confidence intervals for population pharmacokinetic parameters. I: a use of bootstrap standard error. Stat Med 18(5):581–599

    Article  PubMed  CAS  Google Scholar 

  32. West GB, Brown JH, Enquist BJ (1997) A general model for the origin of allometric scaling laws in biology. Science 276(5309):122–126

    Article  PubMed  CAS  Google Scholar 

  33. West GB, Brown JH, Enquist BJ (1999) The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 284(5420):1677–1679

    Article  PubMed  CAS  Google Scholar 

  34. Anderson BJ, Holford NH (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332. doi:10.1146/annurev.pharmtox.48.113006.094708

    Article  PubMed  CAS  Google Scholar 

  35. Hu TM, Hayton WL (2001) Allometric scaling of xenobiotic clearance: uncertainty versus universality. AAPS PharmSci 3(4):E29. doi:10.1208/ps030429

    Article  PubMed  CAS  Google Scholar 

  36. Ritschel WA (1988) Gerontokinetics: pharmacokinetics of drugs in the elderly and aged. Telford Press, Caldwell

    Google Scholar 

  37. Kadokura T, den Adel M, Krauwinkel WJ, Takeshige T, Nishida A (2008) The effect of paroxetine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects. Eur J Clin Pharmacol 64(6):605–609. doi:10.1007/s00228-008-0472-z

    Article  PubMed  CAS  Google Scholar 

  38. Pritchard JF, Bryson JC, Kernodle AE, Benedetti TL, Powell JR (1992) Age and gender effects on ondansetron pharmacokinetics: evaluation of healthy aged volunteers. Clin Pharmacol Ther 51(1):51–55

    Article  PubMed  CAS  Google Scholar 

  39. Koch KM, Corrigan BW, Manzo J, James CD, Scott RJ, Stead AG, Kersey KE (2004) Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors. Aliment Pharmacol Ther 20(2):223–230. doi:10.1111/j.1365-2036.2004.02031.x

    Article  PubMed  CAS  Google Scholar 

  40. Dixon CM, Colthup PV, Serabjit-Singh CJ, Kerr BM, Boehlert CC, Park GR, Tarbit MH (1995) Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab Dispos 23(11):1225–1230

    PubMed  CAS  Google Scholar 

  41. Schwartz JB (2003) The influence of sex on pharmacokinetics. Clin Pharmacokinet 42(2):107–121. doi:10.2165/00003088-200342020-00001

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a Grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A070001).

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Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, South Korea

    Seong Heon Lee, Soo Young Cho, Kyung Yeon Yoo & Seongwook Jeong

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Correspondence to Seongwook Jeong.

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Lee, S.H., Cho, S.Y., Yoo, K.Y. et al. Population pharmacokinetics of ramosetron. J Pharmacokinet Pharmacodyn 43, 73–83 (2016). https://doi.org/10.1007/s10928-015-9455-8

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