Journal of Anesthesia

, Volume 32, Issue 5, pp 709–716 | Cite as

Rocuronium pharmacodynamic models for published five pharmacokinetic models: age and sex are covariates in pharmacodynamic models

  • Kenichi MasuiEmail author
  • Sayaka Ishigaki
  • Atsuko Tomita
  • Hiroshi Otake
Original Article



Equilibration rate constant is necessary to calculate effect-site concentration, which is useful to control drug effect. We developed pharmacodynamic models for published five compartmental pharmacokinetic models published by Wierda, Szenohradszky, Cooper, Alvarez-Gomez, and McCoy.


We used 3848 train-of-four ratios from 15 male and nine female patients (21–76 years; 44–93 kg body weight; 148–181 cm height; and 17.3–29.8 kg/m2 body mass index) as pharmacodynamic measures, which were collected at the start of 0.6 mg/kg rocuronium administration until the end of the surgery. Effect compartment was assumed to be connected to central compartment of the pharmacokinetic model with equilibration rate constant (ke0). Sigmoid Emax model was fitted to describe the relationship between train-of-four ratio and effect-site concentration. Age, sex, and body mass index were assessed as possible covariates of the following model parameters: ke0, effect-site concentration for half of maximum effect, and the steepness of the effect-site concentration versus effect relationship.


The duration of neuromuscular monitoring was 69 (37–129) [median (range)] min. All pharmacodynamic models included age and three included sex as significant covariates. Ke0 values ranged between 0.0820 and 0.247 depending on the pharmacokinetic model. The time-courses of the effect-site concentration were similar among the pharmacodynamic models for Wierda, Cooper, and Alvarez-Gomez pharmacokinetic models, which were lower than that for the Szenohradszky pharmacokinetic model.


Each pharmacodynamic model with the corresponding pharmacokinetic model can be described the time course of rocuronium effect appropriately. The required effect-site concentration of rocuronium for a pharmacodynamic effect was depending on the applied models.


Neuromuscular blockade Rocuronium Pharmacodynamics 


Author contributions

Kenichi Masui: designed and conducted the study, analyzed and interpreted the data, and drafted and revised the manuscript. Sayaka Ishigaki: interpreted the data, and revised the manuscript. Atsuko Tomita: interpreted the data, and revised the manuscript. Hiroshi Otake: interpreted the data, and revised the manuscript.

Compliance with ethical standards

Conflict of interest

Support for this study was solely provided by departmental and institutional funding of Department of Anesthesiology, National Defense Medical College, Tokorozawa, Saitama, Japan. Kenichi Masui is an Editor of the Journal of Anesthesia, and an associate editorial board member of the British Journal of Anaesthesia.


  1. 1.
    Proost JH. Pharmacokinetic–pharmacodynamic modelling of anesthetic drugs. In: Absalom AR, Mason KP (eds) Total intravenous anesthesia and target controlled infusions: a comprehensive global anthology. Cham: Springer; 2017. pp 117–45.CrossRefGoogle Scholar
  2. 2.
    Glen JB, Engbers FHM. The influence of target concentration, equilibration rate constant (ke0) and pharmacokinetic model on the initial propofol dose delivered in effect-site target-controlled infusion. Anaesthesia. 2016;71:306–14.CrossRefGoogle Scholar
  3. 3.
    Minto CF, Schnider TW, Gregg KM, Henthorn TK, Shafer SL. Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics. Anesthesiology. 2003;99:324–33.CrossRefGoogle Scholar
  4. 4.
    Wierda JM, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S. The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Can J Anaesth. 1991;38:430–5.CrossRefGoogle Scholar
  5. 5.
    Szenohradszky J, Fisher DM, Segredo V, Caldwell JE, Bragg P, Sharma ML, Gruenke LD, Miller RD. Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation. Anesthesiology. 1992;77:899–904.CrossRefGoogle Scholar
  6. 6.
    Cooper RA, Maddineni VR, Mirakhur RK, Wierda JM, Brady M, Fitzpatrick KT. Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (Org 9426) during isoflurane anaesthesia in patients with and without renal failure. Br J Anaesth. 1993;71:222–6.CrossRefGoogle Scholar
  7. 7.
    Alvarez-Gomez JA, Estelles ME, Fabregat J, Perez F, Brugger AJ. Pharmacokinetics and pharmacodynamics of rocuronium bromide in adult patients. Eur J Anaesthesiol Suppl. 1994;9:53–6.PubMedGoogle Scholar
  8. 8.
    McCoy EP, Mirakhur RK, Maddineni VR, Wierda JM, Proost JH. Pharmacokinetics of rocuronium after bolus and continuous infusion during halothane anaesthesia. Br J Anaesth. 1996;76:29–33.CrossRefGoogle Scholar
  9. 9.
    Kleijn HJ, Zollinger DP, van den Heuvel MW, Kerbusch T. Population pharmacokinetic–pharmacodynamic analysis for sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade. Br J Clin Pharmacol. 2011;72:415–33.CrossRefGoogle Scholar
  10. 10.
    Vermeyen KM, Hoffmann VL, Saldien V. Target controlled infusion of rocuronium: analysis of effect data to select a pharmacokinetic model. Br J Anaesth. 2003;90:183–8.CrossRefGoogle Scholar
  11. 11.
    Plaud B, Proost JH, Wierda JM, Barre J, Debaene B, Meistelman C. Pharmacokinetics and pharmacodynamics of rocuronium at the vocal cords and the adductor pollicis in humans. Clin Pharmacol Ther. 1995;58:185–91.CrossRefGoogle Scholar
  12. 12.
    Ishigaki S, Masui K, Kazama T. Saline flush after rocuronium bolus reduces onset time and prolongs duration of effect: a randomized clinical trial. Anesth Analg. 2016;122:706–11.CrossRefGoogle Scholar
  13. 13.
    Fuchs-Buder T, Claudius C, Skovgaard LT, Eriksson LI, Mirakhur RK, Viby-Mogensen J. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:789–808.CrossRefGoogle Scholar
  14. 14.
    Masui K. How to select a PK/PD model. In: Absalom AR, Mason KP (eds) Total intravenous anesthesia and target controlled infusions: a comprehensive global anthology. Cham: Springer. 2017. pp 171–87.CrossRefGoogle Scholar
  15. 15.
    Furuya T, Suzuki T, Kashiwai A, Konishi J, Aono M, Hirose N, Kato J, Ogawa S. The effects of age on maintenance of intense neuromuscular block with rocuronium. Acta Anaesthesiol Scand. 2012;56:236–9.CrossRefGoogle Scholar
  16. 16.
    Baykara N, Şahin T, Alpar R, Solak M, Toker K. Evaluation of intense neuromuscular blockade caused by rocuronium using posttetanic count in male and female patients. J Clin Anesth. 2003;15:446–50.CrossRefGoogle Scholar
  17. 17.
    Xue FS, Tong SY, Liao X, Liu JH, An G, Luo LK. Dose-response and time course of effect of rocuronium in male and female anesthetized patients. Anesth Analg. 1997;85:667–71.CrossRefGoogle Scholar
  18. 18.
    Sasakawa T, Masui K, Kazama T, Iwasaki H. The predictive ability of six pharmacokinetic models of rocuronium developed using a single bolus: evaluation with bolus and continuous infusion regimen. J Anesth. 2016;30:620–7.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2018

Authors and Affiliations

  1. 1.Department of AnesthesiologyShowa University School of MedicineTokyoJapan
  2. 2.Department of AnesthesiologyNational Defense Medical CollegeTokorozawaJapan
  3. 3.Department of AnesthesiologySelf Defense Force Yokosuka HospitalYokosukaJapan

Personalised recommendations