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Dose-dependency of PK/PD parameters after intravenous bolus doses of cisatracurium
- Christopher JR Parker (16 December 2008)
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Christopher JR Parker, Consultant Anaesthetist Royal Liverpool and Broadgreen University Hospital
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I would like to congratulate Drs. Chen, Yamaguchi and Varin on their analysis of the kinetics and dynamics of cisatracurium (BJA 2008; 101(6): 788-797). This study provides a serious test of the standard PK/PD model, with good data gathered in a design that maximizes disequilibrium between plasma and effect compartments – a large bolus dose. Figure 7 clearly illustrates the problem with the standard model. The model fitted to data obtained after a low dose fails to explain the data gathered after a high dose – especially during onset. The observed onset of bock is delayed compared to model predictions. There are good biological reasons for this. As the authors point out, the neuromuscular junction contains an excess of post-junctional receptors. Many of these must be occupied before any neuromuscular block occurs (1). This is clinically relevant because: a) A patient can apparently recover normal neuromuscular function and still have circulating non-depolarizing relaxant. b) It has proven hard to find a non-depolarizing relaxant with a rapid onset. The dose-dependent parameter values reflect model mis-specification. The standard sigmoid Emax model is mis-specified, because it takes no account of the fact that a certain drug concentration is required before any effect is observed. A simple way to do this is to model the effect as a sigmoid function of the extent by which the effect compartment concentration exceeds a threshold term (2). The threshold model resolved a similar discrepancy in the model fit to onset data as that found by Chen, though the discrepancy was less dramatic because the data were gathered under conditions much nearer equilibrium – a low dose infusion. 1. Paton WDM and Waud DR, "The margin of safety of neuromuscular transmission" Journal of Physiology 1967; 191: 59 - 90. 2. Parker CJR and Hunter JM, "A new four-parameter threshold model for the plasma atracurium concentration-response relationship" British Journal of Anaesthesia 1992; 68: 548-554. Conflict of Interest:None declared |
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