Comparison of different methods to evaluate population dose-response and relative potency: Importance of interoccasion variability

Different mixed-effects models were compared to evaluate the population dos e-response and relative potency of two albuterol inhalers. Bronchodilator r esponse was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-e ffects (E-max) model with interindividual and interoccasion variability (IO V) in the different pharmacodynamic parameters,vas also fit to the data. Bo th methods produced a similar estimate of relative potency. However, the es timate of relative potency was 22% lower,vith the nonlinear mixed-effects m odel if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates o f ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Further more, the linear mix ed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could a ccount for IOV. Results of the simulations were consistent with those of th e experimental data. Although the lineal or the nonlinear mixed-effects mod el may be used to evaluate population dose-response and relative potency, t here are important differences in the assumptions made by each method.