A turnover longitudinal model for the analysis of FEV1 changes in COPD
M.A. Boroujerdi (1), C. van Kesteren (1), A. Facius (2), M. Danhof (1), O.E. Della Pasqua (1,3)
(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: The forced exhaled volume in one second (FEV1) is the most reproducible test in spirometry and it is commonly used for the assessment of disease severity in chronic obstructive pulmonary disease (COPD). The objective of this investigation was to characterise the changes in FEV1 up to a year from start of treatment using a second order turnover model. Model parameters are estimated for a population of COPD patients following placebo treatment and the effect of drugs simulated on different parameters.
Methods: Data from 3065 COPD patients treated with placebo were evaluated. The lungs are represented as compartment with a FEV1 "turnover". The model assumes that the turnover of lungs is inherently controlled by a turnover or feedback mechanism. The rate constant (k) charactering the turnover was estimated using the second order model. The mechanism of the lungs turnover was further postulated to be nonlinear with saturating turnover with increasing FEV1. The basal value of FEV1 was used as the capacity for the nonlinear model. The controls for the nonlinear model are on the turnover for lungs and the rate constant charactering the flow.
Results: The rate constant charactering the flow is estimated as k=2.446 + 1.268 per/week (Mean + SD). The k estimates were regressed with the subject specific variables and the results are shown in the following table.
| Estimate | CV% | P |
intercept | 2.864 | 7.44 | <0.001 |
Gender (female) | -0.278 | 18.34 | <0.001 |
Ex-smoker* | -0.441 | 10.88 | <0.001 |
Non-smoker* | 0.994 | 12.77 | <0.001 |
age | -0.005 | 63.82 | 0.067 |
BMI | 0.006 | 66.66 | 0.171 |
*The smoking status is compared to the current smokers.
Conclusions: .The FEV1 changes with time are described with a non-linear model based on the turnover and flow rate constant. This model provides the basis for a mechanism based simulation of FEV1 in clinical trials.
