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01 December 2004

Analysis of the pharmacodynamic parameters in a model for neuromuscular block

Vladimir Nigrovic, Anton Amann, Rainhard Bengez

Med Sci Monit 2004; 10(12): BR468-476 :: ID: 13227

Abstract

Background:The study examines the roles of the pharmacodynamic parameters and of the assumptions underlying the pharmacokinetic-pharmacodynamic model proposed by Sheiner and coworkers to interpret the time course of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants.Material/Methods:The model of Sheiner et al. was modified by considering (a) a multiexponential equation for the time course of the relaxant’s concentrations in plasma, (b) the transport of a hypothetical muscle relaxant from plasma to the site of action via diffusion, and (c) NMB as a function of the relaxant’s concentration at the site of action, of γ and IC50. The feasibility of obtaining reliable estimates of the PD parameters was evaluated for either a complete or an incomplete NMB.The model of Sheiner et al. was modified by considering (a) a multiexponential equation for the time course of the relaxant’s concentrations in plasma, (b) the transport of a hypothetical muscle relaxant from plasma to the site of action via diffusion, and (c) NMB as a function of the relaxant’s concentration at the site of action, of γ and IC50. The feasibility of obtaining reliable estimates of the PD parameters was evaluated for either a complete or an incomplete NMB.Results:The results confirmed that reliable estimates of the PD parameters, i.e., of the transport rate constant, γ, and IC50, may be obtained simultaneously if NMB is incomplete. Estimates of the same parameters obtained from a complete NMB are interdependent and, hence, unreliable. The assumptions in the original model of (i) a negligibly small amount of the relaxant in the effect compartment, (ii) steady state plasma concentration at half-maximal NMB, Cp[sub]SS[/sub](50), and (iii) transport of the muscle relaxant from the effect compartment to “Outside”, are neither needed nor are justified.Conclusions:The model proposed by Sheiner et al. interprets well the time course of an incomplete NMB even without the three assumptions. The simulations suggest methods to verify independently the estimates for the transport rate constant and γ.

Keywords: Animals, Computer Simulation, Dose-Response Relationship, Drug, Inhibitory Concentration 50, Models, Biological, Neuromuscular Blockade, Neuromuscular Nondepolarizing Agents - pharmacokinetics, Animals, Computer Simulation, Dose-Response Relationship, Drug, Inhibitory Concentration 50, Models, Biological, Neuromuscular Blockade, Neuromuscular Nondepolarizing Agents - pharmacokinetics

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