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

S Schiere, JH Proost, J Roggeveld, M Wierda*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

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) mug 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: k(ip) 0.374 min(-1) (46%), k(ei) 0.151 min(-1) (36%), EC50 98 mug L-1 (29%) and gamma 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.

Original languageEnglish
Pages (from-to)882-891
Number of pages10
JournalEuropean Journal of Anaesthesiology
Volume21
Issue number11
Publication statusPublished - Nov-2004
EventAnnual Meeting of the American-Society-of-Anesthesiologists - , Canada
Duration: 14-Oct-200018-Oct-2000

Keywords

  • neuromuscular non-depolarizing agents
  • mivacurium
  • pharmacology
  • pharmacokinetics
  • pharmacodynamics
  • cholinesterases
  • pharmacokinetics
  • PLASMA CHOLINESTERASE ACTIVITY
  • NEUROMUSCULAR BLOCKING-AGENTS
  • TIME-COURSE
  • ONSET TIME
  • MODEL
  • DRUGS
  • PHARMACOLOGY
  • METABOLITES
  • ANESTHESIA
  • VECURONIUM

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