We appreciate the interest of Drs. Parker and Hunter in our article on the pharmakokinetics of alcuronium. In their comments two topics are addressed.
Pharmacokinetic modeling. Recent publications emphasize the analysis of combined pharmacodynamic-pharmacokinetic data as a valuable means to validate the pharmacokinetic model [1-3]. Likewise, our studies, which included the data of neuromuscular block and renal elimination of the muscle relaxant into the mathematical iteration, resulted in less variability of the pharmacokinetic parameters than iteration of the plasma concentration-time data alone. Furthermore, the fitting of the effect data to the muscle relaxant concentration in a peripheral compartment rather than in the plasma modified also the relationship between the pharmacokinetic parameters of the two peripheral compartments, including volumes and microconstants.
As shown in our paper , we obtained a significantly better fit using a three-compartment pharmacokinetic model with the effect attached to the superficial peripheral compartment than using a two-compartment model. By contrast, using a two-compartment model with an effect compartment attached to the central compartment, as proposed by Sheiner et al. , resulted in a drug transfer of about 30% from the central compartment into the effect compartment. This finding is incompatible with Sheiner's concept of a negligible volume of the effect compartment.
Concentration-effect relationship. With TOPFIT  we correlated the effect with concentration according to the equation: y = Emax centered dot C (H/IC)50H + CH, resulting in a sigmoid curve, typical for drug receptor interactions. There will certainly be a minimum drug concentration to induce a measurable neuromuscular block. Such a threshold concentration may vary with the method and sensitivity of recording such as twitch tension, electromyography, and different stimulating patterns (e.g., single twitch, train-of-four ratio, tetanic stimulation). Bearing this limited precision of clinical neuromuscular monitoring in mind, we refrained from further increasing the complexity of the data without significant gain in the validity of the model.
Christoph Diefenbach, MD*
Martin Theisohn, MD dagger
Thomas Kunzer, PhD dagger
Christoph W. Buzello dagger
*Departments of Anesthesiology and dagger Pharmacology, University of Koln, D-50931 Koln, Germany
1. Heinzel G, Brickl R, Degner B. Simultaneous fitting of pharmacokinetic and pharmacodynamic data by means of user defined compartment models. In: Heinzel G, Woloszak R, Thomann P. TOPFIT 2.0 Pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart: Gustav Fischer, 1993:82-100.
2. Shargel I., Yu ABC. Applied biopharmaceutics and pharmacokinetics. 3rd ed. Norwalk, CT: Appleton & Lange, 1993.
3. Sheiner LB, Ludden TM. Population pharmacokinetics/-dynamics. Ann Rev Pharm Toxicol 1992;32:185-209.
4. Diefenbach C, Kunzer Th, Buzello CW, Theisohn M. Alcuronium: a pharmacodynamic and pharmacokinetic update. Anesth Analg 1995;80:373-7.
5. Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modelling and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 1979;25:358-71.
6. Heinzel G, Woloszak R, Thomann P. TOPFIT 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the PC. Stuttgart: Gustav Fischer, 1993.