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Purpose. To explore, by simulation procedures, the feasibility of characterizing, from sparse data, the concentration-effect relationship of drugs with pharmacodynamic hysteresis. Methods. For computer simulations, the concentration-effect relationship was assumed to be describable by the Sigmoid-E max equation, the site of drug action was located in a distinct effect compartment (k eo = 10 × k elim), and the pharmacokinetics were those of either a linear one- or two-compartment system. In view of the poor estimability of the parameters of the Sigmoid-E max model under the usual clinical conditions, central compartment post-distributive drug concentrations required to elicit various intensities of effect within the therapeutic range were used as data descriptors. Effect intensities of 5 and 25, or 25 and 50 units (with the “unknown” E max = 100 units) were targeted in multiple-dose (steady state) trial designs. From these data, drug concentrations required to produce effect intensities of 15 and 50 units were estimated by both log-linear and linear interpolation and the actual effect intensities produced by these concentrations were calculated. These simulations were performed over a wide range of Hill coefficient values (0.5 to 4.0) and dosing intervals (0.1 to 1.5 × elimination t 1/2). Results. Acceptable results could be obtained by measuring drug concentrations and effect intensities at or near the end of a dosing interval. The largest deviations of effective concentration estimates (in terms of effect intensity) occurred at a Hill coefficient value of 0.5 and the results were very little affected by changing the dosing interval. Conclusions. Our results demonstrate that effect-controlled clinical trials, with sparse data, of drugs with pharmacodynamic hysteresis for determining concentration-effect relationship in the therapeutic range are feasible in principle.

Since many intravenous anesthetic drugs alter blood flows, physiologically-based pharmacokinetic models describing drug disposition may be time-varying. Using the commercially available programming software MATLAB, a platform to simulate time-varying physiological pharmacokinetic models was developed. The platform is based upon a library of pharmacokinetic blocks which mimic physiological structure. The blocks can be linked together flexibly to form models for different drugs. Because of MATLAB's additional numerical capabilities (e.g. non-linear optimization), the platform provides a complete graphical microcomputer-based tool for physiologic pharmacokinetic modeling.