Modeling of circadian effect on lung function in patients with chronic obstructive pulmonary disease

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Methods: Lung function (FEV1 and FVC) was determined in 14 patients with COPD (mean (SD) age 63 (10) years, post-albuterol FEV1 49 (10) %predicted). FEV1 and FVC were measured at –1 hour pre-time zero, at 5, 15, 30 and 45 minutes post-time zero, and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8 and 12 hours post-time zero on day -1 and day 9. Time zero was around 8:00AM. The change in lung function within 24 hours was analyzed by several models using a nonlinear mixed effects modeling program.  Goodness-of-fit was assessed by evaluating diagnostic plots.

Results: The lung functions (FEV1 and FVC) followed a circadian rhythm in patients with COPD, and this process was adequately characterized using a cosine function. The typical rhythm-adjusted 24-hr mean baseline effect was related to gender, height and age. The typical amplitude for the cosine terms, which expressed as a change from the mean, was 139 mL for FVC and for 96 mL FEV1. The typical time shift for the cosine terms was 7.6 hour for FVC and 7.14 hour for FEV1. The goodness-of-fit plots indicated that the model provided a relatively unbiased fit to the data.

Conclusion: Lung function appeared to show a circadian effect in patients with COPD. It is important to consider this effect when calculating the post-dose drug effect for any drug to treat patients with COPD.