Hostname: page-component-78c5997874-mlc7c Total loading time: 0 Render date: 2024-11-20T04:34:51.807Z Has data issue: false hasContentIssue false
  • English
  • Français

An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium

Published online by Cambridge University Press:  28 January 2005

S. Schiere ,
J. H. Proost ,
J. Roggeveld  and
M. Wierda
S. Schiere
Affiliation:
University Hospital Groningen, Department of Anesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands Present address: De Tjongerschans General Hospital, Heerenveen, The Netherlands.
J. H. Proost
Affiliation:
University Hospital Groningen, Department of Anesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
J. Roggeveld
Affiliation:
University Hospital Groningen, Department of Anesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
M. Wierda
Affiliation:
University Hospital Groningen, Department of Anesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
Get access

Abstract

Summary

Background and objective: The time course of action of mivacurium does not correlate with its rapid breakdown by plasma cholinesterase. Pharmacokinetic–pharmacodynamic (PK–PD) modelling was applied to obtain more insight in the concentration–effect relationship.

Methods: Fourteen patients between 25 and 55 yr, undergoing non-major surgery, American Society of Anesthesiologists Grade I–II, were included. All patients received thiopentone/fentanyl/isoflurane/oxygen/nitrous oxide anaesthesia. Neuromuscular block was monitored mechanomyographically using single twitch stimulation (0.1 Hz). Mivacurium was administered as a short-term infusion, mean (standard deviation) duration 4.7 (1.0) min and dose 145 (33) μg kg−1. Arterial blood samples were obtained, and plasma was analysed using high performance liquid chromatography. PK–PD modelling was performed using an iterative Bayesian two-stage approach, assuming that the trans–trans and cis–trans isomers are equally potent.

Results: A PK–PD model with an effect compartment linked to plasma did not fit to the data satisfactorily. A model using an interstitial space compartment between plasma and effect compartment fitted significantly better. Parameters (mean (percentage coefficient of variation)) of the best fitting model were: kip 0.374 min−1 (46%), kei 0.151 min−1 (36%), EC50 98 μg L−1 (29%) and γ 3.7 (22%).

Conclusions: The PK–PD behaviour of mivacurium could be described using a model with an interstitial space compartment interposed between plasma and effect compartment. This model shows that the time course of mivacurium is mainly governed by the concentration decline in this interposed compartment and only indirectly related to the rapid plasma clearance.

Keywords

NEUROMUSCULAR NON-DEPOLARIZING AGENTS, mivacuriumPHARMACOLOGY, pharmacokinetics, pharmacodynamicsCHOLINESTERASES, pharmacokinetics
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 21 , Issue 11 , November 2004 , pp. 882 - 891
Copyright
2004 European Society of Anaesthesiology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

Part of this study was presented as a poster at the Annual Meeting of the American Society of Anesthesiologists on 16 October 2000 in San Francisco, CA by Schiere S, Proost JH, Wierda M. An alternative approach is necessary to model the concentration–effect relationship of mivacurium. Abstract A538.

References

Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 1979; 25: 358–371.Google Scholar
Venitz J. Pharmacokinetic–pharmacodynamic modeling of reversible drug effects. In: Derendorf H, Hochhaus G, eds. Handbook of Pharmacokinetic/Pharmacodynamic Correlation.Boca Raton, FL: CRC Press Inc, 1995: 1–34.
Laurin J, Donati F, Nekka F, Varin F. Peripheral link model as an alternative for pharmacokinetic–pharmacodynamic modeling of drugs having a very short elimination half-life. J Pharmacokinet Pharmacodyn 2001; 28: 7–25.Google Scholar
Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988; 68: 723–732.Google Scholar
Lien CA, Schmith VD, Embree PB, Belmont MR, Wargin WA, Savarese JJ. The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1994; 80: 1296–1302.Google Scholar
Østergaard D, Rasmussen SN, Viby-Mogensen J, Pedersen NA, Boysen R. The influence of drug-induced low plasma cholinesterase activity on the pharmacokinetics and pharmacodynamics of mivacurium. Anesthesiology 2000; 92: 1581–1587.Google Scholar
Nijs N, Duvaldestin P, Slavov V, Dhonneur G. Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity? Acta Anaesthesiol Scand 1998; 42: 1175–1179.Google Scholar
Proost JH, Wierda JMKH, Meijer DKF. An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs. J Pharmacokinet Biopharm 1996; 24: 45–77.Google Scholar
Beaufort TM, Nigrovic V, Proost JH, Houwertjes MC, Wierda JMKH. Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block. Anesthesiology 1998; 89: 707–714.Google Scholar
Van den Broek L, Wierda JMKH, Smeulers NJ, van Santen GJ, Leclerq MGL, Hennis PJ. Clinical pharmacology of rocuronium (Org 9426): study of the time course of action, dose requirement, reversibility, and pharmacokinetics. J Clin Anesth 1994; 6: 288–296.Google Scholar
Schiere S, Proost JH, Schuringa M, Wierda JMKH. Pharmacokinetics and pharmacokinetic–dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488). Anesth Analg 1999; 88: 640–647.Google Scholar
Lacroix M, Tu TM, Donati F, Varin F. High-performance liquid chromatographic assays with fluorometric detection for mivacurium isomers and their metabolites in human plasma. J Chromatogr B 1995; 663: 297–307.Google Scholar
Viby-Mogensen J, Ostergaard D, Donati F, et al. Pharmocokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP). Acta Anaesthesiol Scand 2000; 44: 1169–1190.Google Scholar
Kleef UW, Proost JH, Roggeveld J, Wierda JMKH. Determination of rocuronium and its putative metabolites in body fluids and tissue homogenates. J Chromatogr B 1993; 621: 65–76.Google Scholar
Mentre F, Gomeni R. A two-step iterative algorithm for estimation in nonlinear mixed-effect models with an evaluation in population pharmacokinetics. J Biopharm Stat 1995; 5: 141–158.Google Scholar
Bennett JE, Wakefield JC. A comparison of a Bayesian population method with two methods as implemented in commercially available software. J Pharmacokinet Biopharm 1996; 24: 403–432.Google Scholar
Akaike H. An information criterion. Math Sci 1976; 14: 5–9.Google Scholar
Unadkat JD, Bartha F, Sheiner LB. Simultaneous modeling of pharmacokinetics and pharmacodynamics with nonparametric kinetic and dynamic models. Clin Pharmacol Ther 1986; 40: 86–93.Google Scholar
Donati F, Meistelman C. A kinetic–dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs. J Pharmacokinet Biopharm 1991; 19: 537–552.Google Scholar
Campkin NTA, Hood JR, Feldman SA. Recovery of mivacurium and doxacurium versus vecuronium in the isolated forearm. Anaesthesia 1994; 49: 501–502.Google Scholar
Feldman SA, Hood JR, Campkin NTA, Rehm S. Sensitivity to second dose of mivacurium. Anaesthesia 1994; 49: 671–674.Google Scholar
Feldman S. Biophase binding: its effect on recovery from non-depolarising neuromuscular block. Anaesth Pharmacol Rev 1993; 1: 81–87.Google Scholar
Hull CJ. Pharmacodynamics of non-depolarizing neuromuscular blocking agents. Br J Anaesth 1982; 54: 169–182.Google Scholar
Ezzine S, Donati F, Varin F. Mivacurium arteriovenous gradient during steady state infusion in anesthetized patients. Anesthesiology 2002; 97: 622–629.Google Scholar
Nigrovic V, Banoub A, Diefenbach C, Mellinghof H, Buzello W. Onset of the neuromuscular block simulated in an anatomical model. Br J Clin Pharmacol 1997; 43: 55–63.Google Scholar
Beaufort TM, Nigrovic V, Proost JH, Houwertjes MC, Kleef UW, Wierda JMKH. Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling? J Pharmacokinet Biopharm 1999; 27: 173–190.Google Scholar
Nigrovic V, Banoub M. Onset of the nondepolarizing neuromuscular block in humans: quantitative aspects. Anesth Analg 1993; 76: 85–91.Google Scholar
Nigrovic V. Neuromuscular block by vecuronium: simulation with a flow–volume model. Eur J Anaesthesiol 1994; 11: 65–74.Google Scholar
Østergaard D, Viby-Mogensen J, Pedersen NA, Holm H, Skovgaard LT. Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients. Acta Anaesthesiol Scand 2002; 46: 684–691.Google Scholar
Ledowski T, Wulf H, Ahrens K, et al. Neuromuscular block and relative concentrations of mivacurium isomers under isoflurane versus propofol anaesthesia. Eur J Anaesthesiol 2003; 20: 821–825.Google Scholar