Designs for population pharmacodynamics: value of pharmacokinetic data and population analysis.

Analyses of simulated data from pharmacokinetic/pharmacodynamic (PK/PD) studies varying with respect to the amount and timing of observations were undertaken to assess the value of these design choices. The simulation models assume mono- or biexponential drug disposition, and Emax-type pharmacodynamics. Data analysis uses a combined PK/PD population analysis or a hybrid, individual-PK/population-PD analysis. Assuming that the goal of the PK/PD studies is to estimate population PD, performance of designs is judged by comparing the precision of estimates of population mean PD parameters and of their interindividual variability. The simulations reveal that (i) PK data, even in small number (2 points per person from as few as 25-50% of persons) are very valuable for estimating population PD; (ii) designs involving more individuals, even if many are sparsely sampled, dominate designs calling for more complete study of fewer persons; (iii) the population analysis is generally superior to the hybrid analysis, especially when the PK model is misspecified (biexponential assumed to be monoexponential for analysis); (iv) varying sampling times and doses among subjects protects against the ill effects of model misspecification. In general, the results are quite encouraging about the usefulness of sparse data designs to estimate population dose response.