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(Chest. 2006;130:54S-64S.)
© 2006 American College of Chest Physicians

Developing the Ideal Inhaled Corticosteroid*

Franklin Cerasoli, Jr, PhD

* From Altana Pharma AG, Florham Park, NJ.

Correspondence to: Franklin Cerasoli, Jr., PhD, Corporate Senior Director, Global Respiratory Medical Affairs, Altana Pharma AG, 210 Park Ave, Florham Park, NJ 07932; e-mail: frank.cerasoli{at}altanapharma-us.com


   Abstract
TOP
 Abstract
Introduction
 Ciclesonide: Pharmacologic,...
 Clinical Expression of the...
 Participant Feedback and...
 Conclusion
 References
 
Inhaled corticosteroids (ICS) are considered the most effective asthma therapy, but concerns remain about side effects. The ideal ICS would have a larger therapeutic ratio than currently available agents, allowing doses to be increased but without greatly increasing the frequency or severity of adverse events. The ideal ICS would possess the following pharmacokinetic properties to maximize efficacy and minimize side effects: high pulmonary deposition, conversion to an active metabolite, high receptor potency, high pulmonary retention, low oral bioavailability, extensive metabolism, and rapid elimination. The new ICS ciclesonide has been shown to possess many of these characteristics. Ciclesonide has also been shown to improve lung function, to treat the underlying inflammation, to be effective as monotherapy in patients with persistent asthma, to have reduced side effects compared with other ICS, and to be easy to use with once-daily dosing. However, as with all new products, the advantages witnessed in clinical trials still have to be demonstrated to be beneficial long-term in general clinical use. ICS with an improved therapeutic index may have the potential to increase patient adherence, enhance the use of ICS monotherapy in the primary care setting, and increase the range of patients for whom ICS monotherapy would be appropriate.

Key Words: asthma • ciclesonide • inflammation • inhaled corticosteroids


   Introduction
TOP
 Abstract
 Introduction
Ciclesonide: Pharmacologic,...
 Clinical Expression of the...
 Participant Feedback and...
 Conclusion
 References
 
Asthma is now widely recognized as an inflammatory disease123 (see article in this supplement by Canonica). The inflammatory process, which involves redundant pathways that use various effector cells, cytokines, and proinflammatory mediators, leads to alterations in large and small airways structure, with thickening of the walls. Lumen narrowing is further compromised by excessive mucus production and deposition as well as the presence of inflammatory exudate.

Inhaled corticosteroids (ICS) effectively and reproducibly repress the inflammatory processes and therefore have a central role in the treatment of asthma. They have potent and pleiotropic antiinflammatory activity enabling downregulation of all redundant pathways. ICS improve lung function and reduce symptoms, exacerbations, hospital readmissions, and mortality caused by asthma.45 ICS are considered the most effective asthma therapy,6 and for these reasons ICS are first-line therapy for control of asthma in all patients with persistent disease.

However, ICS fail to enjoy a favorable reputation in terms of safety and tolerability (see article by Irwin and Richardson in this supplement on the side effects of ICS). Inhaled steroid therapy has been responsible for local side effects including oral candidiasis and dysphonia.7 At the moderate and high doses required to treat some patients with asthma, ICS can produce systemic side effects related to their pharmacologic interactions on the hypothalamic-pituitary axis.89 Many patients have a "steroid phobia" that is based on the local and systemic adverse events from high-dose ICS or oral steroids.10 This can lead to poor compliance; only 33.8% of patients in the United States starting ICS adhere to the therapy.11 Poor compliance may be associated with poor asthma outcomes and is a significant risk factor for asthma morbidity and mortality12 (see article in this supplement by Horne). Therefore, an ideal steroid—one that provides a higher therapeutic ratio with high potency, excellent efficacy, and optimum safety and tolerability—remains an unmet medical need.

One way to meet this need is to widen the therapeutic window of ICS by improving their potency and safety profile to provide a higher therapeutic ratio. The therapeutic index of each ICS is primarily a function of the pharmacokinetic parameters of the drug.13 Agents demonstrating an improved pharmacokinetic profile (ie, high clearance rate, high volume of distribution, and a high level of protein binding, together with a short elimination half-life and a long terminal half-life) have the potential to offer an improved therapeutic index as a result of increased receptor binding affinity, slower absorption from the lung following inhalation, and rapid systemic clearance.14 In turn, this would be expected to manifest as prolonged, targeted antiinflammatory activity in the lung without a concomitant rise in systemic adverse events.14 However, it is also unknown whether some of the efficacy of high-dose inhaled therapy may indeed be due to systemic absorption.

Many steroids have been developed and made available to treat asthma over the last 30 years. They include budesonide, beclomethasone dipropionate (BDP), fluticasone propionate, triamcinolone acetonide, mometasone, and flunisolide. Each has unique physicochemical properties that confer distinct pharmacologic characteristics regarding potency, efficacy, safety, tolerability, lung deposition,65 receptor binding,44 high protein binding,66 protein kinase parameters,16 and lipophilicity and esterfication67 (Table 1 ).15161718192021222324252627 For example, fluticasone propionate is recognized as the most potent ICS and has low bioavailability.28 These activities come from the multiple fluorines, carbothioate, and 17{alpha}-propionyloxy groups.28 Fluticasone, however, as with other ICS, is still associated with some local and systemic side effects, such as oral candidiasis, hoarseness and throat irritation, reduced bone mineral density, glaucoma, and cataract formation.29 BDP has the advantage of being converted to a more active metabolite in the airway by hydrolysis to the mono-ester beclomethasone-17-monoproprionate (BMP).28 Furthermore, one formulation of BDP is in a hydrofluoroalkane metered-dose inhaler, which improves the amount of active drug reaching the lung.30 However, BMP undergoes further metabolism to beclomethasone, which has approximately the same glucocorticoid receptor affinity as dexamethasone.31 Budesonide is a potent steroid that has high pulmonary retention by virtue of reversible lipid esterification.32 Treatment with budesonide, however, can lead to local side effects in the oropharyngeal cavity,33 as well as cortisol suppression at moderate doses.34 Mometasone is a potent ICS with high binding to plasma proteins within the systemic circulation.15


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  		Table 1.. Comparison of the Pharmacokinetic and Pharmacodynamic Features of ICS*

 
Over the past 30 years, from structure/activity relationship studies13141516171819202122232425262728293031323334 of ICS, the ideal physicochemical properties of a new generation of ICS have been identified (Table 2 ). In theory, all of these properties could be engineered into a single ICS in such a way that no single property is compromised. The resulting ICS could possess unique pharmacokinetic and pharmacodynamic properties that render it pharmacologically distinct from currently available ICS. Such an ICS has the potential for a higher therapeutic ratio with high efficacy and improved safety and tolerability. A larger therapeutic ratio than currently available agents would allow doses to be increased without greatly increasing the frequency or severity of adverse events. Safer ICS therapy has the potential to increase patient adherence, enhance the use of ICS monotherapy in the primary care setting, and increase the range of patients for whom ICS monotherapy would be appropriate, thus resulting in the achievement of safe and effective asthma management.


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  		Table 2.. Ideal Properties of ICS

 

   Ciclesonide: Pharmacologic, Pharmacokinetic, and Pharmacodynamic Properties
TOP
 Abstract
 Introduction
 Ciclesonide: Pharmacologic,...
Clinical Expression of the...
 Participant Feedback and...
 Conclusion
 References
 
Ciclesonide is an example of a new-generation ICS. It has been designed and synthesized to include the ideal properties listed in Table 2. These properties provide unique pharmacologic, pharmacokinetic, and pharmacodynamic profiles for ICS.

Pulmonary Deposition
Ciclesonide is formulated as a solution in an hydrofluoroalkane-driven pressurized metered-dose inhaler. In all, 52% of the delivered ciclesonide dose is deposited in the lung.35 Pulmonary deposition of ciclesonide is similar in healthy volunteers and asthmatics.3536 Approximately 38% of the ciclesonide dose remains in the oropharyngeal cavity.35 The high pulmonary deposition is similar to that observed with BDP administered via hydrofluoroalkane pressurized metered-dose inhaler.37 Compared to observations with ciclesonide, the mean lung deposition of fluticasone and budesonide using a metered-dose inhaler is 12% and 18%, respectively, and using a dry powder inhaler is 8% and 30 to 32%, respectively.383940 Such low pulmonary deposition effectively limits the antiinflammatory activity in the treatment of asthma and may increase the dose needed for efficacy, which may also impact on safety and tolerability.

In addition, high pulmonary deposition means low deposition in the oropharyngeal cavity. As mentioned above, approximately 38% of the delivered dose deposits at this site.35 Systemic oral bioavailability of the active metabolite of ciclesonide, desisobutyryl-ciclesonide (des-CIC), is < 1% following oral administration.16 After inhalation of ciclesonide, when compared with IV administration, ciclesonide had an absolute systemic bioavailability of 18% and des-CIC had a systemic availability of 50%.17 Of the newer ICS, limited oral bioavailability is a feature most prominent with fluticasone. These observations imply that both local and systemic side effects with ciclesonide may be limited compared to other ICS.

On-Site Activation and Glucocorticoid Receptor Affinity
Ciclesonide is converted in the lung by hydrolysis of the ester bond at C21 via carboxyl and choline esterases found in cells and epithelial lining fluid of the airways.41 Cells demonstrated to facilitate this conversion include inflammatory cells and epithelial cells.4142 This conversion produces the active metabolite des-CIC. In this way, ciclesonide is similar to BDP, which is converted to an active metabolite (BMP) in the lung by similar mechanisms. However, as mentioned earlier, BMP is further metabolized in the lung to another active drug, beclomethasone.31 des-CIC is not further metabolized in the lung. Conversion of ciclesonide to des-CIC increases the affinity for the glucocorticoid receptor by 100-fold.42 des-CIC has a Ki for this receptor of 0.31 nmol/L,42 which is similar to that of fluticasone, BMP, and budesonide, the most potent ICS available (Table 3 ).314344 des-CIC has the antiinflammatory properties expected from an ICS.4546 Among these properties, which are well characterized in experimental in vitro and in vivo systems, is inhibition of the proliferation of inflammatory cells and the release of inflammatory mediators, including tumor necrosis factor-{alpha}, interleukin-4, and interleukin-5 in vitro.444748 This activity has been associated clinically with decreased sputum eosinophil levels.49


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  		Table 3.. Relative Binding Affinity of Corticosteroids to Rat Glucocorticoid Receptor*

 
The conversion of the limited amount of ciclesonide in the oropharyngeal cavity is virtually nonexistent. Only approximately 5.5% of the deposited ciclesonide is converted to the active metabolite des-CIC. Compared to fluticasone or budesonide,20 which are both fully active in the oropharyngeal cavity, des-CIC is present at levels that are 12.5-fold50 and 25-fold20 lower, respectively. This further implies that oropharyngeal side effects should be low.

Isomers
Like all synthetic compounds, ciclesonide can exist in both the (R)- and (S)-isomer configuration. In accordance with pharmacologic investigations and regulatory guidance, the (R)-isomer and its active metabolite, des-CIC, which is also of the (R)-configuration, were selected for development. Both compounds have higher affinity for the glucocorticoid receptor than their respective (S)-isomers.31 As a consequence, the (S)-isomer of ciclesonide was removed from clinical preparations, as it contributes little to the clinical pharmacology of ciclesonide. It is unknown whether (S)-ciclesonide and its active metabolite confer any adverse pharmacologic activity as do laternatate isomers, such as (S)-albuterol, (R)-thalidomide, and some others.

Protein Binding
Protein-bound molecules are pharmacologically inactive, as only free drug is able to interact with the receptor. Thus, the ideal corticosteroid should possess high protein binding to minimize the potential for interaction with systemic receptors, which can lead to adverse events once the drug is absorbed from the lung. With BDP, budesonide and fluticasone propionate, 10 to 13% of the circulating drug is free and unbound.51 More than 99% of ciclesonide, however, is protein bound, resulting in a > 10-fold difference in the amount of free drug in the circulation compared with other ICS (Fig 1 ).1851


Figure 1
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  		Figure 1.. Protein binding of ICS1851: ciclesonide (CIC), des-CIC, fluticasone propionate (FP), budesonide (BUD), BDP, and triamcinolone acetonide (TAA).

 
Pulmonary Retention
Corticosteroids, such as budesonide, that have a hydroxyl group at C21 can form reversible esters with fatty acids in the lungs. The lipid-conjugated ICS is retained in the lung, intercalating into cell membranes. Although the lipid conjugate of des-CIC is not active, lipid conjugation increases pulmonary residence time and provides a local depot in the lung for slow release. Because of its conversion in the lung to the active metabolite des-CIC, which in turn undergoes reversible lipid conjugation to form a fatty acid ester des-CIC oleate, ciclesonide has a long duration of action. In human lung slices 2 to 24 h after dosing, as the concentration of ciclesonide declines, the concentrations of des-CIC and the lipid conjugate increase, so that at 24 h approximately 50% is lipid conjugate, approximately 30% is active metabolite, and approximately 15% is ciclesonide.52

Oral Deposition and Bioavailability
To minimize the systemic effects of any swallowed portion of the drug, the ideal corticosteroid should have low oral bioavailability. Two separate studies have compared the oral deposition of ciclesonide with fluticasone50 and budesonide.20 In both studies, the oral deposition of ciclesonide was significantly less than the other steroids. Furthermore, ciclesonide was not extensively converted to des-CIC, resulting in only 8%50 and 4%20 of the deposition of budesonide and fluticasone, respectively. This low oral deposition and minimal activation may lead to less pharyngitis/laryngitis and oral candidiasis than with other ICS.

A study16 evaluating the absolute bioavailability of ciclesonide has also been conducted. This shows that this bioavailability is < 1% of the administered dose.16 Certainly, some of this low bioavailability is due to the low rate of oral deposition. However, other mechanisms, such as limited intestinal absorption and extensive first-pass metabolism, undoubtedly contribute to limiting the availability.

Pharmacokinetics, Metabolism, and Elimination
Ciclesonide and des-CIC have very different pharmacokinetic profiles. The circulating concentration of des-CIC is only 10% of the total circulating concentration of ciclesonide, and only approximately 1% of that is unbound to plasma protein and able to interact with systemic receptors.16 The systemic exposure of patients to des-CIC, defined by the area under the curve, is about one quarter of that of ciclesonide. The half-life of des-CIC is approximately 3 h.53 As with other ICS, ciclesonide is metabolized and cleared rapidly by the liver; cytochrome P450 enzymes metabolize des-CIC to inactive metabolites (Fig 2 ).26 des-CIC has high (> 99%) first-pass metabolism in the liver, and 77.9% of the dose is recovered in the feces.17 These findings all suggest that the systemic exposure to active des-CIC that is able to interact with systemic receptors is very low.


Figure 2
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  		Figure 2.. Ciclesonide metabolism. Reproduced with permission.26

 
Summary of Design Properties
Ciclesonide has been shown to possess many pharmacokinetic and physicochemical characteristics that may make it an ideal ICS: high pulmonary deposition, conversion to an active metabolite, high receptor potency, high pulmonary retention, low oral bioavailability, metabolized elsewhere in the body, and rapid and extensive elimination. Each of these features contributes to the overall efficacy, safety, and tolerability of ciclesonide. Clinical studies345051545556 have shown that these properties have translated into clinical benefits; however, as with all new products, only its clinical use over the long-term will reveal potential outcome advantages in terms of asthma control, exacerbations, and disease progression.


   Clinical Expression of the Pharmacologic Properties of Ciclesonide
TOP
 Abstract
 Introduction
 Ciclesonide: Pharmacologic,...
 Clinical Expression of the...
Participant Feedback and...
 Conclusion
 References
 
Clinical Efficacy of Ciclesonide
Several studies have shown that ciclesonide improves lung function in patients with asthma. A 12-week, double-blind, randomized, parallel-group study54 found that ciclesonide (160 µg/d or 640 µg/d) administered in the morning effectively maintained asthma control (peak expiratory flow, FEV1, and FVC) vs placebo in 329 adults with persistent asthma. In another study,55 ciclesonide at 160 µg qd in either the morning or the evening for 8 weeks improved FEV1 in patients with mild-to-moderate asthma (Fig 3 ). Additionally, asthma symptom scores and use of rescue medication were reduced from their baseline values (p < 0.001 and p < 0.01, respectively). The efficacy provided by the once-daily administration is believed to be due to the pulmonary retention of ciclesonide, although there may be the possibility that, at high dose, some of the efficacy of ciclesonide could be due to systemic absorption. In other investigations, ciclesonide also demonstrated improved lung function and measures of asthma symptoms and control. These included improvements in FEV1 that were maintained over 1 year and lack of any exacerbation in 85% of the patients over the same period.56


Figure 3
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  		Figure 3.. The effects of ciclesonide, 160 µg qd, in the morning (am) or evening (pm) on FEV1 in patients with asthma. Reproduced with permission.55 Intent-to-treat population data are presented as means.

 
Clinical Efficacy of Ciclesonide Compared With Other Current "Gold Standard" ICS
Clinical trials have also compared the efficacy of ciclesonide with other current "gold standard" ICS. One investigation57 demonstrated that ciclesonide, 160 µg qd in the morning, was as effective as budesonide, 200 µg bid, at improving FEV1, asthma symptom score, and rescue medication use. Comparison of equivalent doses of ciclesonide or budesonide (320 µg) administered once daily in the evening over 12 weeks in patients with mild-to-moderate asthma demonstrated that ciclesonide afforded approximately a 25% greater improvement in FEV1 (Fig 4 ) and comparable improvements in asthma symptom score and rescue medication use.58 The onset of improvement in pulmonary function afforded by ciclesonide was faster (3 days) than for budesonide (14 days). These data suggest that the potency of ciclesonide is twice that of budesonide on a dose basis. Additionally, the efficacy is achieved with a once-daily vs twice-daily dosing regimen. Any difference between the efficacy of ciclesonide and budesonide undoubtedly arises from the differences in their physicochemical properties that produce differing pharmacologic and pharmacokinetic characteristics.


Figure 4
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  		Figure 4.. Comparison of the effect of 12 weeks of treatment with ciclesonide at 320 µg qd in the evening, and budesonide at 400 µg qd in the evening on FEV1 in patients with mild-to-moderate asthma. Reproduced with permission.58 Intent-to-treat population data are presented as least-squared means.

 
The efficacy of ciclesonide administered once daily was comparable to fluticasone administered twice daily, regardless of the dose level. Ciclesonide 320 µg qd in the morning or evening was comparable to fluticasone, 440 µg/d, in decreasing airway hyperresponsiveness as assessed with methacholine.59 In another study,60 ciclesonide, 160 µg, administered in the evening improved FEV1, asthma symptom score, and rescue medication use to levels comparable to that of fluticasone at 200 µg/d. These results suggest that the physicochemical properties of ciclesonide and the pharmacology that they impart enable it to be as efficacious on a once-daily dosing regimen as fluticasone on a twice-daily dosing regimen.

Systemic Exposure of Ciclesonide and Adverse Events Related to Ciclesonide Exposure
The biomarkers demonstrating systemic exposure of ciclesonide and adverse events related to ciclesonide exposure are markedly different to those of other ICS. Serum cortisol is well recognized as a sensitive marker of systemic exposure and bioactivity of ICS, and decreases in serum cortisol suggest hypothalamic-pituitary-adrenal axis suppression. This suppression is related to the systemic activity of ICS, which may be linked to their systemic side effects. These effects often minimize the therapeutic window of ICS and lead to disuse and poor asthma control.

Investigations of the systemic exposure of ciclesonide through biomarkers, such as serum cortisol, suggest that at very high doses there is virtually no systemic exposure to bioactive ciclesonide. In the 12-week, placebo-controlled study54 described above, serum and 24-h urine cortisol levels were unaffected by ciclesonide 160 µg or 640 µg administered once daily in the morning, and both doses were well tolerated with adverse event profiles similar to placebo.

Ciclesonide, 320 µg qd, in the morning produced no alteration in urinary cortisol, while budesonide at the same dose produced a significant reduction.57 Similarly, subchronic exposure to ciclesonide doses (1,280 µg/d in the evening for 9 days) 8 to 16 times higher than therapeutic doses (160 µg/d or 80 µg/d, respectively) did not alter serum cortisol levels measured serially (area under the curve) over the course of a day following the last dose.61 This is in contrast to fluticasone, which produced a 30% decrease in serum cortisol at a dose of 880 µg/d and a 60% decrease at 1,760 µg/d.61 These very high doses produced similar inhibition of airway hyperresponsiveness, suggesting, along with the cortisol data described above, that the therapeutic window for ciclesonide is greater than that of fluticasone.

Local Side Effects
Ciclesonide also produces local side effects with only minimal frequency. For example, the incidence of pharyngitis, candidiasis, and dysphonia is either no different to or less than that observed with placebo.62 This is in contrast to local side effects observed in comparative trials with other ICS. In one example, ciclesonide, 640 µg/d, produced an incidence of oral candidiasis of < 1%, whereas fluticasone, 880 µg/d, produced an incidence of approximately 11%.63

Long-term Exposure
In an open-label extension of the 12-week, placebo-controlled study,54 283 patients completing the double-blind phase of this trial or who dropped out due to lack of efficacy received a further 40 weeks of treatment (median ciclesonide dose, 640 µg/d).64 During the 52-week course (initial 12-week study plus 40-week extension), cortisol levels were not suppressed (Fig 5 ).64 Slight increases were reported in 24-h urine cortisol, while serum cortisol was unchanged (Table 4 ).64 During the open-label extension, 24-h urine cortisol increased by 28% (p < 0.05), while serum cortisol levels were unchanged (Table 4). The most frequently reported adverse events affected the respiratory tract and were rated as being unlikely or unrelated to ciclesonide therapy. Overall, the incidence of oropharyngeal adverse events was low and included pharyngitis (4%), voice alteration (2%), and oral candidiasis (1%). In another 1-year study,56 exposure to ciclesonide at an average dose of 1,080 µg/d, which is 6.8- to 13.6-times higher than daily therapeutic doses of 160 µg/d or 80 µg/d, respectively, produced no decrease in serum cortisol suggesting no long-term hypothalamic-pituitary-adrenal axis suppression. These findings demonstrate that long-term treatment with ciclesonide up to 52 weeks had no suppressive effect on the hypothalamic-pituitary-adrenal axis and resulted in a low incidence of oropharyngeal effects.


Figure 5
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  		Figure 5.. Mean 24-h urine cortisol levels (± SEM) over time during a 12-week double-blind study and a 40-week open-label extension study of ciclesonide (median dose, 640 µg/d) in patients with persistent asthma.64

 

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  		Table 4.. Changes in Urine and Serum Cortisol During a 40-Week Open-Label Extension Study of Ciclesonide (Median Dose, 640 µg/d) in Patients With Persistent Asthma*

 
Summary of Clinical Properties
These data on systemic bioactivity and local side effects provide evidence that a unique combination of pharmacologic properties can be built into an ICS that impacts on tolerability. Low oral deposition and exposure, minimized bioactivity in the oropharynx, low systemic bioavailability, and high protein binding all provide characteristics that minimize unwanted pharmacologic activity that can lead to side effects.


   Participant Feedback and Discussion
TOP
 Abstract
 Introduction
 Ciclesonide: Pharmacologic,...
 Clinical Expression of the...
 Participant Feedback and...
Conclusion
 References
 
Workshop participants were asked to discuss the following questions in relation to this presentation:

What factors do you use to assess the efficacy and safety of an ICS?
Is this evaluation different for monotherapy vs other regimens?
How do you factor pharmacokinetic/pharmacodynamic parameters in assessing ICS efficacy and safety?
What are the most critical safety considerations? (bone mineral density, knemometry, oral candidiasis, dysphonia)
To what degree do you differentiate between ICS? What unique attributes does each have?
Is there room for a new ICS in asthma? Please consider specific "gaps" and limitations to current therapy.
What top three qualities should a new ICS have to satisfy your therapeutic expectations?

One of the issues discussed regarding the development of the ideal ICS was the assessment and efficacy of these agents. Efficacy is generally assessed on the basis of improved lung function, symptom control, and frequency of exacerbations, but such measures may be influenced by compliance and inhalation technique. The inhalational device may influence selection, but the choice of agent has to be balanced against the patient’s wishes and acceptance. It was thought that adherence to therapy and requests for treatment refills could be used as measures of efficacy. In general, the literature suggests that all ICS are perceived as being effective. Assessment of efficacy and control is most difficult in patients with very severe asthma. With currently available agents, reimbursement and cost issues appear to have little influence on the choice of agent.

Regarding safety and adverse events, it was recognized that physicians often fail to solicit information proactively on local side effects, and that concerns about systemic side effects were generally lower. Although oral candidiasis is not a major problem, it was believed that this complication should be monitored. Regarding the effects of ICS on bone density, concern is greatest in some elderly patients. Dysphonia is of concern as it causes disruption to the patient’s quality of life, and affected patients may be offered a lower drug dose or a different agent. (The article by Irwin and Richardson discusses the general side effects of ICS in more detail.) Pharmacokinetic and pharmacodynamic data were recognized as being important in the assessment of ICS but need to be reinforced with data on efficacy and control.

The ideal ICS would allow increases in dose with subsequent increases in efficacy but no concomitant increase in the incidence of side effects. Although asthma guidelines reflect the current evidence in favor of combination therapy after moderate dose ICS, the participants thought that safer ICS monotherapy may replace high-dose leukotriene receptor antagonists and combination therapy in the United States. Asthma severity classification was considered of little concern when evaluating the ideal ICS. The participants considered that, in general, safer ICS monotherapy, particularly if administered once daily, is likely to enhance the use of such agents in all asthma patients.


   Conclusion
TOP
 Abstract
 Introduction
 Ciclesonide: Pharmacologic,...
 Clinical Expression of the...
 Participant Feedback and...
 Conclusion
References
 
Asthma remains undertreated. Only therapies targeted toward the underlying inflammation can provide effective asthma treatment that results in improvement of lung function, decreased exacerbations, and meaningful symptom control. ICS are recognized as the cornerstone of antiinflammatory asthma therapy. However, a number of factors, including tolerability, a limited sense that the medication is "working," fears or concerns about the long-term effects of the medication, and complicated dosing regimens, make the regular use of ICS unlikely for any given patient. Many years of accumulated knowledge can enable the design of ICS with physicochemical properties (by virtue of the chemical moieties that comprise the entire molecule) leading to improved and targeted pharmacologic activities. The ideal ICS would possess high pulmonary deposition and on-site activation to provide antiinflammatory activity targeted to the airways; minimal oral exposure and limited activation to provide high local tolerability; and high protein binding to provide limited systemic bioactivity. These properties translate into clinical advantages, such as comparable, if not superior, efficacy to the "gold standard" ICS available today, a very low incidence of local side effects (such as oral candidiasis, dysphonia, and pharyngitis), and virtually no systemic activity as evidenced by maintenance of biomarkers (such as serum and urinary cortisol levels). The ideal ICS is designed with the patient in mind—which has positive implications for persistence and compliance—and aims to deliver effective, optimal antiinflammatory therapy for the treatment of asthma. Ciclesonide is the first of such "designed" ICS, which represents a new generation of steroids. However, as with all new products, the advantages witnessed in clinical trials still have to be demonstrated to be beneficial in general clinical use.


   Acknowledgements
 
The author thanks Jane Davies, PhD, for writing and editorial support in the development of this article.


   Footnotes
 
Abbreviations: BDP = beclomethasone dipropionate; BMP = beclomethasone-17-monopropionate; des-CIC = desisobutyryl-ciclesonide; ICS = inhaled corticosteroids/corticosteroid

Dr. Cerasoli is an employee of Altana Pharma.

Received for publication July 2, 2005. Accepted for publication March 20, 2006.


   References
TOP
 Abstract
 Introduction
 Ciclesonide: Pharmacologic,...
 Clinical Expression of the...
 Participant Feedback and...
 Conclusion
 References
 

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