title: An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium.
abstract: 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 55yr, 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) microg 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 microg 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.
authors.affiliation: Department of Anesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Hospital Groningen, Groningen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Schiere
authors.forename: J H
authors.initials: JH
authors.lastname: Proost
authors.forename: J
authors.initials: J
authors.lastname: Roggeveld
authors.forename: M
authors.initials: M
authors.lastname: Wierda
mesh_terms: D000328:Adult; D001825:Body Fluid Compartments / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005110:Extracellular Space / Q000502:physiology*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077590:Mivacurium; D008954:Models, Biological; D003473:Neuromuscular Nondepolarizing Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D000077590:Mivacurium