Q:

4/3/2014
I have been searching for current information/data on chronobiology/chronopharmacology in asthma (or allergic rhinitis). Some studies in the 1980's and 1990's showed that the best time to treat with inhaled corticosteroids (or oral corticosteroids?) is 1500 or 1730 (or qid) and not 0800. This resulted in improved FEV1 and less effect on the HPA axis. If peak cortisol secretion is between 0400-0800 why is treating with inhaled or oral corticosteroids preferred at 1500 or 1730? Do you know of any other data about chronobiology and chronopharmacology in allergic diseases?

A:

Thank you for your inquiry.

Below you will find three fairly recent reviews on the subject of chronopharmacology and chronobiology. One of these is, as you can see, is specific for allergic diseases.

In addition, I can understand your confusion regarding the most appropriate time to administer inhaled corticosteroids, and I am not sure that I can shed any light on this matter, but I will share with you my perspective of the issues producing this confusion.

I think the decision of when to administer corticosteroids to treat asthma can be based on three separate issues:

1. The route of administration of the steroid.

2. The pharmacodynamics and pharmacokinetics of the steroid (especially its duration of action).

3. Whether you are looking at the most appropriate time to improve outcomes or the most appropriate time to avoid side effects.

The initial studies looking at the optimal time for the administration of corticosteroids were done in children who were given oral corticosteroid preparations. Dr. Hyman Chai and colleagues (see two references below) did most of the groundbreaking work in this regard. They clearly demonstrated that the administration of corticosteroids in the morning, and every other day, resulted in a diminished side effect profile. So I believe that if one is looking at the prevention of side effects from oral steroids, the administration in the morning, mimicking the normal chronobiology, is the optimal dosing time.

However, when one deals with oral steroids that have a 24 to 36 hour pharmacodynamic effect, this beneficial effect is lost. So we learned two facts from this. To prevent side effects when corticosteroids are given orally, the optimal dosing is in the morning and also every other day provided that the drug has a relatively "short half-life". For example, this would apply to prednisone. But if the drug has a long biological half-life, one loses this effect.

When using inhaled corticosteroids, as you know, the systemic effects are diminished considerably with a marked reduction in the effect on growth and other side effects. Thus mimicking the chronobiology to prevent side effects, as one would do when these drugs are administered orally, is not a dominant consideration. The effectiveness of the treatment becomes far more important. And since asthma is a nocturnal disease, it has been hypothesized that the administration of a drug later in the day might be more effective. If you are not as worried about side effects, and you are considering the therapeutic effect, the optimum dosing can change. This is evident by the results obtained from the studies that are abstracted below.

Also, in part, this increased effectiveness may be due to compliance which some authors have hypothesized might be greater if the drug is administered later in the day rather than early in the morning.

Thus, in summary, the "best time to treat with corticosteroids" depends on:

1. The outcome you are assessing.

2. The drug you are using.

3. The route of administration of the drug (in this case, it is really not so much the route of administration, but the fact that by the inhaled route, we can use a far lower dose).

Once again, if you wish a further and more complete review, I think the aforementioned references copied below will be of help to you.

Thank you again for your inquiry and we hope this response is helpful to you.

References:
1. Falliers CJ, Chai H, Molk L, Bane H, Cardoso RR. Pulmonary and adrenal effects of alternate-day corticosteroid therapy. J Allergy Clin Immunol. 1972 Mar;49(3):156-66.

2. Chai H, Gilbert A. The effect of alternate-day prednisone on the white blood count in children with chronic asthma. J Allergy Clin Immunol. 1973 Feb;51(2):65-70.

3. De Giorgi A, Mallozzi Menegatti A, Fabbian F, Portaluppi F, Manfredini R. Circadian rhythms and medical diseases: does it matter when drugs are taken? Eur J Intern Med. 2013 Dec;24(8):698-706. doi: 10.1016/j.ejim.2013.03.019. Epub 2013 Apr 21.

4. Sewlall S, Pillay V, Danckwerts MP, Choonara YE, Ndesendo VM, du Toit LC. A timely review of state-of-the-art chronopharmaceuticals synchronized with biological rhythms. Curr Drug Deliv. 2010 Dec;7(5):370-88. Review.

5. Smolensky MH, Lemmer B, Reinberg AE. Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma. Adv Drug Deliv Rev. 2007 Aug 31;59(9-10):852-82. Epub 2007 Aug 17. Review

Abstract:
Journal of Allergy and Clinical Immunology, Volume 71, Issue 4, April 1983, Pages 425-433.
Circadian changes in effectiveness of corticosteroids in eight patients with allergic asthma.
A double-blind, crossover, randomized, placebo-controlled chronotherapeutic study was designed in which eight patients (two men, 20 and 48 yr old, and six women, 22 to 58 yr old) suffering from corticosteroid-dependent allergic asthma were socially synchronized, with a diurnal activity from about 7:30 a.m. to about 11 p.m., and a nocturnal rest. During an 8 day span they were treated on a Dutimelan 8-15 regimen, labeled DTM 8-15: at 8 a.m. a pill containing 7 mg of prednisolone acetate and 4 mg of prednisolone alcohol, at 3 p.m. a pill with 15 mg of cortisone acetate and 3 mg of prednisolone alcohol, and a placebo at 8 p.m. During another 8 day span they were given a placebo at 8 a.m. and at 3 p.m. a pill with 15 mg of cortisone acetate and 3 mg of prednisolone alcohol and at 8 p.m. another pill with 7 mg of prednisolone acetate and 4 mg of prednisolone alcohol, a regimen labeled Rx 15-20. During wakefulness (between 7 a.m. and 11 p.m.), every 2 hr at eight fixed clock hours, peak expiratory flow (PEF), grip strength, and oral temperature were self-measured and dyspnea, cough, and fatigue were self-rated. The PEF 24 hr mean as well as the nocturnal dip were lower (p < 0.05 to p < 0.0005) with Rx 15-20 than with DTM 8-15, while the nocturnal increase of dyspnea was greater with Rx 15-20 than with DTM 8-15. Long-term administration of corticosteroids at 8 a.m. and 3 p.m. was more effective to control asthma and enhance PEF values than the same agents and dose given at 3 and 8 p.m.

Abstract:
J Allergy Clin Immunol 1995;95:1172-8.
Abstract
Background: Studies in asthma with systemic corticosteroids given at 3:00 PM have shown a superior therapeutic benefit compared with dosing at other time points.
Objective: The study was designed to compare beneficial and systemic effects of 800 μg of inhaled triamcinolone once daily at 3:00 PM (QD group) versus 200 μg conventional four times a day dosing (QID group).
Methods: Efficacy outcome measures included forced expiratory volume in 1 second (FEV 1), peak expiratory flow rates, bronchial responsiveness, and use of β-agonist. Systemic effects were blood eosinophil and cortisol levels, 24-hour urinary cortisol, and evaluation for oral candidiasis and dysphonia.
Results: The baseline FEV 1 was comparable in the two groups: QD = 67% ± 2% and QID = 66% ± 2% of predicted value. After 4 weeks of treatment, FEV 1 increased similarly in the QD group to 77% ± 4% and in the QID group to 74% ± 4% of predicted value. Likewise, the improvement in morning and evening peak expiratory flow rates was not significantly different between the groups. Both QD and QID groups experienced comparable daily decrements in β-agonist use. The systemic responses to the two regimens as assessed by eosinophil count, morning serum cortisol, and 24-hour urinary cortisol were also comparable.
Conclusions: The single daily administration of inhaled triamcinolone at 3:00 PM has no increased systemic effects and produces similar improvement in efficacy variables. A dosing strategy based on once daily dosing should increase compliance of inhaled steroid use in the clinical setting.

Sincerely,
Phil Lieberman, M.D.

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