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University of Dundee, Dundee, Scotland
Dr. Lipworth is Professor of Allergy and Pulmonology, Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee.
Correspondence to: Brian J Lipworth, MD, Professor of Allergy and Pulmonology, Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, DD1 9SY, Scotland, UK; e-mail: b.j.lipworth{at}dundee.ac.uk
Inhaled corticosteroids are recommended as first-line antiinflammatory therapy for the treatment of persistent asthma in children and adults.1 The majority of patients do not experience systemic or local adverse effects at low to medium doses of commonly used inhaled corticosteroids. Attempts have been made by the pharmaceutical industry to refine topically active higher-potency second-generation inhaled corticosteroids, such as fluticasone propionate (FP) and mometasone furoate (MF), with claims of lower systemic bioactivity and hence a superior therapeutic ratio, as compared to the older first-generation drugs such as beclomethasone dipropionate and budesonide. However, clinical studies with FP and latterly MF have shown evidence of predictable dose-related systemic bioactivity such as hypothalamic-pituitary-adrenal (HPA) axis suppression.2345
An increasing concern among prescribers and patients alike is that in susceptible individuals, higher doses of FP have been associated with a clinically relevant degree of adrenal insufficiency and growth retardation.6789 Measuring growth and weight in children is simple to do and should be part of good clinical practice in any child with a chronic disease.
The dilemma for clinicians looking after adult asthmatics in everyday practice is how to identify such at-risk individuals without subjecting all patients to time-consuming and expensive screening tests of HPA axis activity. In many patients who have detectable endogenous cortisol suppression, this merely indicates the presence of exogenous corticosteroid in the systemic circulation, without implying a risk for developing acute adrenal insufficiency on exposure to stressful stimuli.10 Concerns regarding systemic safety have been recognized in asthma guidelines,1 which now advocate the use of lower doses of inhaled corticosteroids, particularly when used with adjunctive second-line controller therapy.
Enter the so-called "designer" third-generation inhaled corticosteroids, such as ciclesonide. A detailed review of the particular pharmacologic and pharmacokinetic properties of ciclesonide is given elsewhere, although there are cogent reasons as to why ciclesonide might exhibit a superior safety profile compared to currently available inhaled corticosteroids.11 Ciclesonide is a prodrug with low glucocorticoid receptor activity, which is activated by esterase activity on site in the lungs to form its active moiety, des-isobutyryl-ciclesonide (des-CIC), which exhibits high glucocorticoid receptor activity, with a relative binding affinity between budesonide and fluticasone.121314 des-CIC is highly lipophilic, which along with formation of intracellular fatty acid conjugates results in prolonged lung tissue retention,15 making it suitable for once-daily dosing. For the dose of ciclesonide deposited in the lungs (approximately 50%), there is extensive absorption from the lungs, with 99% plasma protein binding of des-CIC, as compared to 90% for fluticasone, resulting in a much lower concentration of the free unbound corticosteroid in the systemic circulation.11 For the moiety deposited in the oropharynx and larynx, there is only minimal conversion to des-CIC.11
Consequently, local adverse effects such as oral candidiasis and hoarseness are negligible due the low topical mucosal glucocorticoid activity of the ciclesonide prodrug. Moreover, for the swallowed fraction, there is extensive (99%) inactivation on first pass via the liver, so that oral bioavailability is negligible.11
The study by Dr. Szefler and coworkers16 in this issue of CHEST (see page 1104) set out to investigate the relative effects of 4 weeks of treatment with ciclesonide (640 µg and 1,280 µg daily dose ex-actuator), fluticasone (880 µg and 1,760 µg ex-actuator), or placebo on sensitive measures of basal and dynamic HPA axis activity in 60 patients with moderate-to-severe asthma and a mean FEV1 of 60.6% of predicted. For the primary outcome of 24-h serum cortisol, there was no significant suppression with either dose of ciclesonide. There was significant suppression from baseline only with fluticasone, 1,760 µg, amounting to a 38.5% difference vs placebo, although this was not associated with commensurate attenuation of the dynamic cortisol response to low-dose (1 µg) cosyntropin stimulation.
The results of Szefler et al16 are similar to those in 148 patients with mild-to-moderate asthma (FEV1 82.5% of predicted) receiving 3 months of treatment with either placebo, ciclesonide 320 µg or 640 µg, or fluticasone 880 µg, where a sequential low-dose (1 µg) and high-dose (250 µg) cosyntropin stimulation as well as 24-h urinary cortisol were measured.17 The results showed no significant HPA axis suppression for any test with either dose of ciclesonide, while fluticasone caused significant suppression of the 250-µg cosyntropin response (11.2% suppression) and urinary cortisol (41.0% suppression) vs placebo; but as in the study of Szefler et al,16 it did not affect the 1-µg cosyntropin response. The apparent disconnection in suppression between measures of basal (24-h cortisol) and dynamic (low-dose cosyntropin stimulation) HPA axis function would suggest that even with the highest dose of fluticasone, the findings are unlikely to be clinically relevant in terms of patients being at risk for acute adrenal insufficiency. The absence of any detectable adrenal suppression with ciclesonide seen in the above two studies in asthmatics is also mirrored by previous data showing a lack of effect on 24-h serum cortisol profile in healthy volunteers receiving a dose of 640 µg/d.18
It is worth noting that there is always considerable interindividual variability in the susceptibility to adrenal suppression. Unfortunately, the presented data from Szefler et al16 have not included a scatterplot to illustrate the individual cortisol responses. This is relevant because from a real-life clinical perspective, one deals with an individual rather than average patient. As Dr. Szefler correctly points out, the relatively small degree of suppression in their study probably reflects the reduced lung absorption of fluticasone in severe asthmatics with impaired caliber, as reflected by the low FEV1 of 60.6%. Indeed, in another study19 of patients with severe asthma and a mean FEV1 of 47%, also receiving 1,760 µg of fluticasone per day (via a spacer), there was no suppression of the cortisol response to 100-µg human corticotrophin releasing factor (hCRF) stimulation, compared to 42.2% mean suppression in healthy volunteers receiving the same dose. Interestingly, in patients with severe COPD with (mean FEV1 43%) or without emphysema (mean FEV1 51%) receiving 1,760 µg of fluticasone, there was 40.1% vs 41.0% suppression, respectively, of overnight urinary cortisol.20 One might predict that peripheral absorption would be impaired in COPD, especially in the presence of alveolar destruction due to emphysema, perhaps inferring that at least for fluticasone, absorption may be occurring more proximally. This observation suggests that patients with severe asthma but not COPD may be serendipitously protected from systemic adverse effects with fluticasone, although the mechanism for this discrepancy is unclear.
Another important factor to take into account is the inhaler device, as the respirable dose and particle size will determine the lung bioavailability for any given inhaled corticosteroid. For example, for fluticasone, it has been shown that comparing the relatively coarse particles from the dry powder inhaler to the finer particles from metered-dose inhaler plus spacer will result in up to sixfold-greater adrenal suppression with the latter for the same labeled dose.21 For the hydrofluoroalkane ciclesonide metered-dose inhaler, although the respirable fraction is approximately 50% with an extra-fine particle size of approximately 1 µm, the high degree of lung bioavailability does not translate into commensurate increased systemic bioactivity due to the high protein binding of the (des-CIC) moiety that is absorbed from the lung. However, the ciclesonide inhaler will result in peripheral distribution of extra-fine particles, which in theory may improve antiasthmatic efficacy in patients, where there is a component of small airways inflammation.
The overall therapeutic index of ciclesonide will also be determined by the topical antiasthmatic efficacy, the latter governed by its lung deposition, glucocorticoid potency, and lung retention. In terms of the relative efficacy of fluticasone and ciclesonide, the lower glucocorticoid potency of latter is likely to be offset by its higher deposition and more prolonged lung retention, especially as fluticasone does not form intracellular fatty acid conjugates. The therapeutic index can only be assessed by studies where the relative airway/systemic activities have been evaluated in tandem.
In a study of patients with mild-to-moderate asthma (FEV1 88%) receiving 9 days of fluticasone 880 µg and 1,760 µg daily, there was 29% and 59% suppression, respectively, on 24-h plasma cortisol, and 44% and 60% suppression on 24-h urinary cortisol, relative to placebo, while ciclesonide 640 µg and 1,280 µg had no significant effects.22 Significant improvements in adenosine monophosphate-induced airway hyperreactivity were demonstrated with all treatments, but no differences between doses or drugs.
Lee et al23 compared 4 weeks of ciclesonide, 1,280 µg, vs fluticasone, 1,760 µg, in patients with moderately severe asthma (FEV1 67%), where there were similar improvements on methacholine-induced airway hyperreactivity with both drugs, along with significant suppression of the cortisol response to hCRF stimulation and overnight urinary cortisol after fluticasone but not ciclesonide, amounting to a 33% difference between the drugs for urinary cortisol. Further data in 19 patients with mild-to-moderate asthma (FEV1 84%) showed no difference in antiasthmatic efficacy comparing 4 weeks of either ciclesonide, 320 µg, vs fluticasone, 440 µg, daily on outcomes including methacholine hyperreactivity, exhaled nitric oxide, spirometry, peak flow, and quality of life.24 Taken together, these studies would suggest that ciclesonide has a more favorable overall therapeutic ratio than fluticasone when used at higher doses.
What further work needs to be done to properly define the therapeutic index of ciclesonide? Short-to medium-term dose-response studies are indicated using appropriate sensitive outcome measures of airway and systemic bioactivity on the steep part of the response curve in order to compare ciclesonide with other commonly used inhaled corticosteroids, over the wide range of asthma severities, in order to properly assess their relative therapeutic ratios. In addition, longer-term studies in adults over at least 1 year would be required to look at more clinically relevant outcomes, such as exacerbations, bone density, and cataracts, particularly at higher doses in patients with more severe asthma.
One could argue that a drug such as ciclesonide is arriving at a time when guidelines are advocating the use of lower doses of inhaled corticosteroids, particularly in conjunction with a long-acting ß2-agonist as combination inhalers. In this regard, perhaps the development of a ciclesonide combination inhaler would represent the ideal marriage for efficacy and safety.
Footnotes
The author and other members of the Asthma and Allergy Research Group have received financial support from Altana, Sanofi-Aventis, AstraZeneca, Schering Plough, GlaxoSmithKline, Innovata Biomed, Ivax, Merck, Cipla, and Neolab (who all manufacture inhaled steroids or other antiasthma products) for performing clinical trials, equipment, postgraduate training and education, attending scientific meetings, consulting, and giving lectures.
References
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