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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
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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

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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.

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