Comparison of Different Methods to Evaluate Population Dose–Response and Relative Potency: Importance of Interoccasion Variability
- 138 Downloads
Different mixed-effects models were compared to evaluate the population dose–response and relative potency of two albuterol inhalers. Bronchodilator response 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-effects (Emax) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-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 account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose–response and relative potency, there are important differences in the assumptions made by each method.
Unable to display preview. Download preview PDF.
- 3.International Conference on Harmonization (ICH) Guideline for Industry. Dose-response information to support drug registration. Fed. Reg. 59:55972–55976 (1994).Google Scholar
- 4.D. J. Finney. Statistical Method in Biological Assay, Charles Griffin, London, 1978.Google Scholar
- 7.A. J. Boeckmann, L. B. Sheiner, and S. L. Beal. NONMEM Users Guide Part V, NONMEM Project Group, University of California, San Francisco, 1994.Google Scholar
- 11.W. R. Gillespie, S. G. Machado, D. J. Schuirmann, G. R. Zhu, A. H. Balch, and C. Hu. Bioequivalence assessment based on pharmacodynamic response: Application to albuterol metered-dose inhalers. Pharm. Res. 14:S-139 (1997).Google Scholar