Feasibility of Effect-Controlled Clinical Trials of Drugs with Pharmacodynamic Hysteresis Using Sparse Data

Abstract

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.