Single Afternoon Dose of ICS Linked to Better Lung Function and Reduced Inflammation in Asthma
The chronotherapeutic approach aligns treatment with peak glucocorticoid sensitivity, so may mitigate onset of the inflammatory cascade that triggers nocturnal exacerbations.
A single mid-afternoon dose of inhaled beclomethasone may offer optimal control of asthma by better suppressing the nocturnal worsening of airway obstruction and inflammation, according to results from a small randomized crossover trial published in Thorax.1
Adults with mild to moderate asthma experienced greater improvements in FEV₁ and FEV₁/FVC ratio and larger overnight reductions in blood eosinophil counts when taking a 400 µg dose between 3:00 and 4:00 PM vs morning or twice-daily dosing regimens. Importantly, the benefits of afternoon dosing were observed without exacerbating adrenal suppression, altering serum cortisol rhythms, or increasing adverse events common with corticosteroid use, according to the results.1
For the study, first author Ran Wang, PhD, MRes, MBChB, National Institute for Health and Care Research clinical lecturer, division of immunology, immunity to infection and respiratory medicine, University of Manchester, and colleagues enrolled 25 adults (median age, 42 years, range 18 – 65; 64% men; 76% White) with a confirmed diagnosis of mild to moderate asthma and common respiratory allergies.
Participants completed three 28-day treatment periods, each separated by a 14- to 21-day washout: once-daily morning dosing of beclometasone dipropionate (400 µg between 8:00 and 9:00 AM), once-daily afternoon dosing (400 µg between 3:00 and 4:00 PM), and twice-daily dosing (200 µg between 8:00 and 9:00 AM and again between 8:00 and 9:00 PM). Twenty-one participants (84%) completed all 3 regimens. Investigators measured spirometry readings and blood biomarkers (inflammatory cells, levels of cortisol and salbutamol from reliever inhalers) every 6 hours for 24 hours at the start and end of each of the 28-day periods, according to the study.1
Wang et al reported that all regimens of the inhaled corticosteroid (ICS) improved nighttime lung function compared to baseline; however, the magnitude of improvement was significantly greater with mid-afternoon dosing.
Improvements in FEV₁ were a median 170 mL higher than morning dosing (P <.01) and 60 mL higher than twice-daily dosing (P =.02). The investigators also found that afternoon dosing yielded a 4% greater improvement in FEV₁ percent predicted compared with morning dosing (P <.01) and a 2% greater improvement compared with twice-daily dosing (P =.02). Treatment in the afternoon also led to the most significant improvement in FEV₁/FVC ratio, authors wrote.1
Although peak expiratory flow rates and fractional exhaled nitric oxide (FeNO) levels improved across all regimens, Wang's team said that no significant differences emerged between dosing schedules, an outcome likely the result of the ceiling effects in FeNO suppression. 1
As with other measures, the most pronounced reduction in blood eosinophil (Eos) counts followed afternoon dosing, although the researchers reported a decline across groups. In evening measurements Eos counts were 0.07 × 10⁹ cells/L lower than those recorded for the twice-daily regimen (P <.01). When they looked at morning measurements, Eos counts were 0.04 × 10⁹ cells/L lower (P =.03). Morning dosing also reduced Eos counts compared with twice-daily treatment, though to a lesser extent, according to the results.1
Analyses of the midline statistic of rhythm indicated no significant differences in serum cortisol profiles between regimens. Asthma Control Questionnaire scores assessing change in symptoms improved similarly across all groups. Wang and colleagues also found no difference among the treatment regimens for use of reliever medication or for adverse events, suggesting to the team that midafternoon ICS administration poses no additional safety concerns.1
The investigators propose that chronotherapy, aligning corticosteroid administration with the body’s circadian rhythm, may take advantage of well-recognized periods of increased glucocorticoid sensitivity.
“Our findings further support the hypothesis that the optimal timing of [inhaled corticosteroid] administration is at 16:00, coincident with enhanced glucocorticoid sensitivity at that time,” they said in a statement.2
“The notion that the onset of the inflammatory cascade begins mid-afternoon may also explain the findings we observed, and the attenuation of the predictable rhythmic recruitment of airway inflammatory cells at this time point may abolish the subsequent excessive nocturnal dip in lung function in asthma,” they suggested.2
The authors also acknowledged the study’s limitations, citing the small size, short duration, and relatively mild disease severity among participants, which may limit the generalizability of the findings. They added, however, that their results are in line with prior evidence on circadian influences in asthma. Wang and colleagues emphasized the need for larger efficacy trials, particularly in patients with more severe asthma, to determine whether midafternoon ICS dosing can translate into meaningful clinical gains in symptom control and risk reduction.1 Until larger trials confirm their findings, they recommend not changing current timing of inhaler therapy.
“While midafternoon dosing may be complicated by the challenges around non-adherence in some patients, the advantages of taking ICS at the optimal timing may overcome some of the identified barriers (eg, achieving efficacy with lower cost),” the authors wrote.1
“Our findings also provide key opportunities for novel chronopharmacological and chronotherapeutics development,” they added, that may lead to more individualized therapy “based on individuals’ preference in timing of drug administration and their biological rhythm in disease.”1
