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ANESTHETIC PHARMACOLOGY

Pharmacokinetic/Pharmacodynamic Modeling of Rocuronium in Myasthenic Patients Is Improved by Taking into Account the Number of Unbound Acetylcholine Receptors

Ann De Haes, MD^*, Johannes H. Proost, PharmD PhD^*, Jan B. M. Kuks, MD PhD, David C. van den Tol, MD, and J. Mark K. H. Wierda, MD PhD^*

*Research Group for Experimental Anesthesiology and Clinical Pharmacology and Department of Neurology, University Hospital Groningen, Groningen, The Netherlands; and Department of Anesthesiology, Lievensberg General Hospital, Bergen op Zoom, The Netherlands

Address correspondence and reprint requests to Ann De Haes, MD, Department of Anesthesiology, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. Address e-mail to a.de.haes{at}anest.azg.nl

Patients with myasthenia gravis are more sensitive than healthy patients to nondepolarizing neuromuscular blocking drugs. We performed a pharmacokinetic/pharmacodynamic modeling study of rocuronium in eight myasthenic patients and eight matched control patients. Patients were anesthetized with propofol and sufentanil and a mixture of nitrous oxide/oxygen. Mechanomyographical monitoring of the adductor pollicis was applied. Rocuronium was infused at a rate of 25 µg · kg^-1 · min^-1 in myasthenic patients and 116.7 µg · kg^-1 · min^-1 in control patients and was terminated at 70% neuromuscular block. Arterial blood samples were drawn during onset and offset of the block and for 4 h after the administration of rocuronium. Plasma concentrations were determined by high-performance liquid chromatography. Pharmacokinetic/pharmacodynamic modeling was performed by using the Sheiner model and the unbound receptor model (URM), which takes into account the number of unbound acetylcholine receptors. The effective concentration at 50% effect and the steepness of the concentration-effect relationship were significantly decreased in myasthenic patients. Both the URM and the Sheiner model provided an adequate fit in myasthenic patients. The acetylcholine receptor concentration was significantly decreased in myasthenic patients. The URM explains the observed differences in time course and potency, whereas the Sheiner model does not.

IMPLICATIONS: We performed a pharmacokinetic/pharmacodynamic modeling study in myasthenic patients and control patients. The unbound receptor model, which takes into account the number of unbound acetylcholine receptors in the biophase, was introduced and compared with the model proposed by Sheiner.