POPULATION PHARMACODYNAMICS - STRATEGIES FOR CONCENTRATION-CONTROLLEDAND EFFECT-CONTROLLED CLINICAL-TRIALS

OBJECTIVE: To explore and evaluate various strategies for drug concent ration- and effect-controlled clinical trials, respectively, in the co ntext of studies of population phamacodynamics (concentration-effect r elationships). METHODS: The relative utility of drug concentration- an d pharmacologic effect-controlled, randomized clinical trials with two or three concentration-effect measurements for each subject has been explored by computer simulation. The basis for these simulations was a sigmoid-E(max) (maximum effect) pharmacodynamic model with E(max) = 1 00%, EC(50) (drug concentrations required to produce an effect intensi ty of 50%) = 10 concentration units, gamma = 2, and no hysteresis. E(m ax) and gamma were held constant whereas EC(50) was assumed to be log- normally distributed with a 26% coefficient of variation of the natura l log-normalized data. A smaller random variability and variability du e to measurement error also were incorporated in the simulations. To e xplore the implications of variable and unknown E(max) and gamma value s, the suitability of linear and log-linear interpolation procedures f or two-point concentration-effect data in different regions of the sig moid-E(max) curve was compared. RESULTS: Pharmacologic effect-controll ed clinical trials with 300 hypothetical subjects and targeted effect intensities of 25% and 75% yielded very good estimates of drug concent rations required to produce effect intensities of 35%, 50%, and 65%, w hereas concentration-controlled trials yielded much poorer estimates. Moreover, the concentration-controlled trials, despite optimum choice of targeted concentrations, yielded a large number of data points with poor information content (effect intensities of <15% or >85%). Determ inations based on targeted effect intensities of 25% and 75% yielded b etter estimates of individual EC(50) values than those targeted for 25 % and 50% or 50% and 75% effect intensity. Results were not significan tly improved by adding a third measurement (targeted to 50% effect) to the 25% and 75% effect design. Estimations of drug concentrations req uired to produce an effect intensity of 50%, based on log-linear inter polation of exact concentration-effect data at 25% and 75%, yielded ex act results independent of gamma value (0.5-8.0) whereas linear interp olation produced large overestimates at gamma = 0.5 or 1.0 but satisfa ctory estimates at gamma equal to or greater than 2.0. Similar calcula tions for an effect intensity of 15% based on exact concentration-effe ct data at 5% and 25% yielded reasonably good estimates by both method s of interpolation over a wide range of gamma values. A review of the clinical literature showed that gamma values are usually 2 or higher. CONCLUSIONS: Population pharmacodynamic studies of reversibly acting d rugs without pharmacodynamic hysteresis or time dependency (e.g., tole rance) can be successfully conducted using a pharmacologic effect-cont rolled randomized clinical trial design with only two properly selecte d target effect intensities per subject.