Prediction of drug effects using a longitudinal turnover model for FEV1 in patients with chronic obstructive pulmonary disease (COPD).
C. van Kesteren1, M.A. Boroujerdi1, A. Roy1, A. Facius2, M. Danhof1, O.E. Della Pasqua1,3
(1)Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; (2) Dept. of Pharmacometrics, Nycomed GmbH, Konstanz, Germany; (3) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, United Kingdom.
Objectives: Currently, FEV1 (forced expiratory volume in one second) is widely used for assessment of disease severity and evaluation of treatment response. As part of a model-based analysis, the objective of this investigation was to explore putative drug effects on different model parameters under varying clinical trial conditions, accounting for dropout and other relevant implementation factors.
Methods: Simulation scenarios were evaluated using a turnover model based on data from placebo-treated patients in phase III clinical studies. In addition to the putative drug effect on disease progression, the influence of relevant disease and demographic covariates was explored by varying inclusion and exclusion criteria (i.e., Baseline FEV1, gender, smoking status, age and BMI). A putative symptomatic and a combination of symptomatic and disease modifying effect were tested.
Results: Following placebo treatment and symptomatic treatment, FEV1 decreases with time and age. A gender difference was observed with a faster decline in FEV1 for female patients. Non-smokers do not seem to differ significantly from smokers. In contrast, ex-smokers experienced a faster decline of FEV1 than smokers. The effect of disease-modifying treatment is currently being analysed.
Conclusions: Simulation scenarios with a longitudinal turnover model can be used to predict the decline of FEV1 in COPD patients during the course of treatment in a clinical trial. The approach will serve as a basis to further optimise patient stratification (inclusion/exclusion criteria) and overall clinical trial design for the assessment of efficacy in COPD.