Pharmacotherapy considerations for morning symptoms in chronic obstructive pulmonary disease

Figures & data

Figure 1. Schematic of the theoretical variation in airway caliber due to circadian rhythm and the bronchodilation effect of long-acting (1× or 2× daily) and short-acting (4× daily) therapies. Long-acting bronchodilators lead to an increased net area under curve and higher morning FEV₁ following the last inhalation (trough FEV₁). Administration of bronchodilator at 0800 h (trough) coincides with a lower airway caliber which is hypothesized to worsen morning symptoms. Shifting the time of medication administration may mitigate this effect. Figure 1 adapted with permission from Springer Nature: Kai M. Beeh et al, Advances in Therapy, 2010 [11].

Table 1. Clinical studies that address the impact of medication timing on clinical efficacy in COPD.

Treatment	Study design	Patient population	Outcomes	Reference
Tiotropium bromide 18 mg once daily: (1) 0900 h (Tio-AM) vs. (2) 2100 h (Tio-PM) vs. placebo	6-week, multicenter, double-blind, randomized, placebo-controlled trial	Stable COPD aged ≥40 years and a smoking history of at least 10 pack-years (n = 121; mean FEV1 = 41% predicted)	No significant difference in mean nocturnal or steady state FEV1 or forced vital capacity (FVC) between Tio-AM and Tio-PM groups after 6 weeks.	[5]
Tiotropium (Tio) with or without formoterol (Form): (1) Tio 0800 h vs. (2) Tio 0800 h and Form 2000 h vs. (3) Form 0800 h and 2000 h vs. (4) Tio + Form 0800 h, and Form 2000 h vs. (5) Form 0800 h, and Tio + Form 2000 h	Randomized, blind, crossover study	Stable moderate-to-severe COPD with a smoking history (n = 80; mean post-bronchodilator FEV1 = 54% predicted)	At day 30, Treatment (5) showed the largest mean ∆ FEV1 increase compared to day 1. Treatment (5) showed the least FEV1 variability during the 24 h.	[15]
Sustained-release oral Theophylline: (1) 8 mg/kg at 0700 h and 4 mg/kg at 1900 h vs. (2) 6 mg/kg at 0700 h and 6 mg/kg at 1900 h vs. (3) 4 mg/kg at 0700 h and 8 mg/kg at 1900 h	Randomized, crossover study	Males with COPD and a history of asthma (> 15% response to inhaled β2 stimulants) (n = 12; mean FEV1 84% predicted)	24-h average peak expiratory flow was significantly higher in Treatment (3).	[16]

Beeh KM, Beier J. The short, the long and the “ultra-long”: why duration of bronchodilator action matters in chronic obstructive pulmonary disease. Adv Ther. 2010;27(3):150–159.

 PubMed Web of Science ®Google Scholar

Calverley PMA, Lee A, Towse L, et al. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease. Thorax. 2003;58(10):855–860.

 PubMed Web of Science ®Google Scholar

Terzano C, Petroianni A, Conti V, et al. Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD. Respir Med. 2008;102(12):1701–1707.

 PubMed Web of Science ®Google Scholar

Bruguerolle B, Philip-Joet F, Parrel M, et al. Unequal twice-daily, sustained-release theophylline dosing in chronic obstructive pulmonary disease. Chronobiol Int. 1987;4(3):381–385.

 PubMed Web of Science ®Google Scholar