FEASIBILITY OF EFFECT-CONTROLLED CLINICAL-TRIALS OF DRUGS WITH PHARMACODYNAMIC HYSTERESIS USING SPARSE DATA

Purpose. To explore, by simulation procedures, the feasibility of char acterizing, from sparse data, the concentration-effect relationship of drugs with pharmacodynamic hysteresis. Methods. For computer simulati ons, the concentration-effect relationship was assumed to be describab le by the Sigmoid-E(max) equation, the site of drug action was located in a distinct effect compartment (k(eo) = 10 x k(elim)) and the pharm acokinetics were those of either a linear one- or two-compartment syst em. 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 inten sities of effect within the therapeutic range were used as data descri ptors. Effect intensities of 5 and 25, or 25 and 50 units (with the '' unknown'' E(max) = 100 units) were targeted in multiple-dose (steady s tate) trial designs. From these data, drug concentrations required to produce effect intensities of 15 and 50 units were estimated by both l og-linear and linear interpolation and the actual effect intensities-p roduced by these concentrations were calculated. These simulations wer e performed over a wide range of Hill coefficient values (0.5 to 4.0) and dosing intervals (0.1 to 1.5 X elimination t(1/2)). Results. Accep table results could be obtained by measuring drug concentrations and e ffect intensities at or near the end of a dosing interval. The largest deviations of effective concentration estimates (in terms of effect i ntensity) 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 feasib le in principle.