Once-Daily Inhaled Corticosteroids in the Treatment of Asthma: Weighing the Risk-Benefit Relationship

Introduction

Peter J. Barnes, M.D., Professor of Thoracic Medicine at the Imperial College London in London, England began the symposium by stating, “asthma is a highly complicated chronic inflammatory disease involving many inflammatory cells that are activated in the airways.” These inflammatory cells release multiple mediators that can affect the airway wall (i.e., bronchoconstriction, vasodilatation, mucous secretion, plasma leakage, sensory nerve activation) while chronic stimulation of these mediators can lead to structural changes to the asthmatic airways (i.e., fibrosis, increased smooth muscle, increased mucous secreting cells, and increased vessels). Dr. Barnes further stated, “if you treat the patient with inhaled steroids you can resolve this inflammation,” adding, “in mild asthma, this can be resolved completely so that all the inflammatory cells disappear from the airway mucosa and the airway epithelium grows back as normal.”

One biomarker that illustrates the connection between inflammation and asthma is nitric oxide in the patient’s breath. “This is because the inflammation of asthma induces the enzyme nitric oxide synthase, which makes large amounts of nitric oxide and leads to the increased concentration in the breath,” declared Dr. Barnes. When steroids are administered, nitric oxide levels return to normal levels and when steroid administration is discontinued, the inflammation returns and nitric oxide levels increase. “So this is telling you that steroids work in asthma by suppressing inflammation,” said Dr. Barnes.
Steroids achieve this effect by having a very broad spectrum of anti-inflammatory actions such as inhibiting the release of inflammatory mediators as well as their recruitment, and survival. Inhaled steroids accomplish these multiple anti-inflammatory actions within the lung cells. “When you inhale the steroid, it crosses the cell membrane and binds to glucocorticoid receptors,” stated Dr. Barnes. Within the cell, activation of these receptors creates a cascade of events that can alter gene expression. “The major effect of steroids that we are looking at when we treat asthma patients is suppression of multiple inflammatory genes which could be coding for cytokines, adhesion molecules, or inflammatory enzymes like iNOS,” acknowledged Dr. Barnes. These effects, however, are not due to steroids acting directly on the gene, as previously thought. Instead, steroids act indirectly and Dr. Barnes used the remainder of his introduction to discuss one mechanism by which steroids inhibit specific factors that stimulate inflammatory response genes. That is, during an inflammatory response, the transcription factor nuclear factor-k-B opens the chromatin structure surrounding the DNA to allow inflammatory genes to be transcribed. Steroids stimulate histone deacetylase-2 (HDAC-2) that switch off those activated inflammatory genes by returning the chromatin structure back to its resting state and blocking transcription. “You can’t do anything to improve this mechanism because this is nature’s way of controlling inflammation,” stated Dr. Barnes, adding, “so the only improvement you can achieve is by pharmacokinetic manipulation and what the rest of this symposium is about is how we can optimize the pharmacokinetics of inhaled steroids to harness these remarkable molecular effects in the safest and most effective way.”

The Pharmacokinetic Basis For Once-Daily Dosing Of Inhaled Corticosteroids

The pharmacodynamics of inhaled steroids refers to the concentration of the drug at the glucocorticoid receptor site and its effects. In this regard, dose and receptor-binding properties are important as is a good biomarker to quantify the results. In contrast, pharmacokinetics is concerned with the concentration of the drug in the blood and how long it remains there. For this, the drug’s clearance, absorption and distribution properties are important. Combining these properties, pharmacokinetic/pharmacodynamic (PK/PD) models are used to determine what dose to use for the measured effect over time.

Hartmut Derendorf, Ph.D., Professor and Chairman of the Department of Pharmaceutics at the University of Florida in Gainesville, FL, used three common steroids, methylprednisolone, dexamethasone, and triamcinolone acetonide, to illustrate the importance of PK/PD models to assess steroids’ safety and efficacy. Using these 3 steroids, each with different receptor binding properties and clearance values, Dr. Derendorf showed the audience that neither high receptor binding alone, clearance alone, nor dose alone can determine the safest and most efficacious drug. Rather it is a combination of these and other properties of the steroid that determine the best medication.

Dr. Derendorf used the remainder of his presentation on PK/PD models to explain how drug and drug delivery properties of inhaled steroids can determine which once-daily medication is safe and effective for the treatment of asthma.

Pulmonary residence time
One way to develop a safe and effective once-daily inhaled steroid is to increase its pulmonary residence time. This keeps the steroid in the lung longer where it is effective and away from other organs where it causes systemic adverse effects. There are different ways to increase pulmonary residence time. For example, one method is to develop a drug that dissolves very slowly in the lung (e.g., lipophilic drugs and prodrugs). A second method is to develop drugs that can reversibly form lipophilic fatty acid conjugates (e.g., budesonide, ciclesonide). A third method is to develop a drug that can utilize a drug delivery system that slowly releases the drug into the lungs (liposomes, microspheres).

A unique approach to increase pulmonary residence time has been employed by the steroid ciclesonide. It is a prodrug that is converted to the active steroid, desisobutyryl-ciclesonide, in the lung. Once in the cell, some of the active drug is further converted to a lipophillic ester that keeps it in an inactive state in the cell. Slowly, the ester is cleaved and the drug can interact again with the glucocorticoid receptors in the lung. In this way, pulmonary residence time is increased to improve drug efficacy in the lung and possibly decrease systemic adverse effects.

Systemic effects
Safety is also a concern with steroids and an excellent biomarker for the systemic side effects of inhaled steroids is cortisol. Using PK/PD models, Dr. Derendorf showed the audience that the steroid, the dose, and the time of day the steroid is given can significantly alter its effect on cortisol suppression. “The reason for that is because we are dealing with a circadian rhythm of cortisol,” explained Dr. Derendorf. For example, if you dose once a day with budesonide in the evening, there is less cortisol to suppress and the overall effect on cortisol is smaller. “The time of dosing is important for a steroid with a short half-life,” concluded Dr. Derendorf. Cortisol suppression with fluticasone is similar whether it is given in the morning or at night because fluticasone has a long half-life. In contrast, flunisolide, with a shorter half-life, has a greater effect in the morning than the evening. Interestingly, cortisol suppression with ciclesonide is very small. This is due to this compound having 10-fold higher plasma protein-binding properties compared to other available steroids. As a result, the amount of free ciclesonide in the system is low and it has a very small cortisol effect. In addition to the limited effect on cortisol levels, the high plasma binding property of ciclesonide means that it can be taken in the morning or evening, and the minimal effect on cortisol will be the same. In a recent study, a comparison of 800 µg ciclesonide given in the morning, 800 µg ciclesonide given in the evening, and 400 µg ciclesonide twice a day showed no significant differences in cortisol suppression (J Clin Endocrinol Metab. 2002;87:2160).

Concluding remarks
Dr. Derendorf ended his presentation saying, “I believe that once a day dosing of inhaled corticosteroids is a convenient way to go.” Slow dissolution by certain formulations or taking advantage of the intrinsic mechanisms of lipids and/or ester formations in the lung can significantly improve safety and efficacy of these drugs.

The Evidence for Once-Daily Dosing of Inhaled Corticosteroids: A Critical Review of Literature

As we move towards an era of more convenient dosing, more aggressive dosing, and earlier intervention, many clinicians are concerned about the long-term adverse effects of inhaled steroids. This is especially true for treating asthmatic children. This concern may be exacerbated by the growing trend to use once-daily inhaled steroids. “There is a whole host of adverse effects if you were to read the package insert but the ones that clinicians really focus in on are growth delay, ocular disorders such as ocular hypertension, cataracts, and bone disorders such as osteoporosis,” said Stanley Szefler, M.D., Head, Division of Clinical Pharmacology/Immunopharmacology at the National Jewish Medical and Research Center in Denver, CO. Accordingly, clinicians need to examine the balance of efficacy with safety when choosing a medication for their patients.

Once-daily dosing has several potential advantages, including: convenience; reduced risk of adverse events; and lower costs. In addition, once-daily dosing can improve compliance which reduces the concern for undertreatment of asthma that can lead to:

• Increased risk of acute exacerbations
• Poor asthma control
• Exercise-induced bronchospasm
• Possible irrecoverable loss of lung function

With that being said, simply because a drug can be given once a day and improve compliance in patients, does not necessarily mean that it is safer or more efficacious than multi-dose medication. To address this issue, Dr. Szefler presented an overview of the pivotal studies comparing once- versus twice-daily dosing with fluticasone or budenoside and the general message was that once-daily dosing was effective but generally not as effective as twice-daily dosing although adherence to treatment may be slightly improved with once-daily dosing. Dr. Szefler cautioned the audience by saying that most of these studies compared same total day doses and in some preparations, slightly higher doses of the once-daily medication would be more effective. Unfortunately, dose response curves comparing once- versus twice-daily regimens have not been performed.

Another concern with clinicians is the uncertainty of how, when, and for whom switching twice-daily to once-daily dosing regimens should be performed. Although data is limited, Dr. Szefler showed the audience a small study comparing efficacy of once daily steroids in patients who previously were given steroids and in patients with no history of steroid use. Both patient groups had similar efficacy with once-daily regimens. Dr. Szefler advised that when starting treatment with a once-daily steroid, however, the initial dose should be fairly high and once asthma control is achieved, a lower dose may be considered.

In children, Dr. Szefler stated that once-daily steroid use is effective for mild asthma but in more serious asthmatic children, the once-daily regimens do not appear to be as effective but more studies are needed.

Dr. Szefler ended his presentation by stating that it is best to start most patients with twice-daily dosing and reduce to once-daily or lower doses as tolerated by the patient. Dr. Szefler hoped that as we develop better measures to monitor inflammation and asthma, the transition from multiple dosing to once-daily dosing should become easier.

Choosing an Inhaled Corticosteroid for Once-Daily Administration

Søren Pedersen, MD, PhD, Professor of Pediatric Respiratory Medicine at the University of Southern Denmark, in Kolding, Denmark concluded the symposium with a further discussion on deciding which once-daily inhaled steroid to use. Reiterating what was stated by Dr. Szefler, Dr. Pedersen added, “there is an amazing lack of good comparative studies on once-daily dosing between different steroids.” Until such studies are performed, clinicians are forced to examine each drug separately and make an appropriate decision. One method is to measure how long the inhaled drug is retained in the lungs. Several factors influence that, including the amount of drug deposited in the airways, the lipophilicity of the drug and the ability to form a depot of inactive drug. In regard to lung deposition, delivery system is important. For example, lung deposition of various once-daily medications are: 10% (fluticasone DPI); 20% (fluticasone MDI); 30% (budensonide DPI); and 50% (ciclesonide HFA, beclomethasone HFA).

In regard to lipophilicity, a steroid with high lipophilicity will theoretically stay in the lung longer than less lipophilic steroids. In terms of lipophilicity, ciclesonide is the most lipophilic inhaled corticosteroid , followed by fluticasone, beclomethasone, budesonide and then triamcinolone.

A final factor that contributes to a long pulmonary residence time is whether the steroid can be reversibly converted to an inactive form, which will act as a depot in the lung. Dr. Pedersen used the example of budesonide to show that although it has lower lipophilicity compared to beclomethasone or fluticasone, it stays longer in the lung. This occurs because a percentage of the free budesonide undergoes esterification and forms an inactive complex that is reactivated later when concentrations of free budesonide decline. A similar conversion occurs with ciclesonide where approximately 25% of the drug undergoes esterification.

Theoretically, an examination of lung deposition, lipophilicity, and conjugate properties for the various steroids suggests that ciclesonide should be one of the best steroids available for once- daily dosing (Table 1). However, its use in the clinical setting needs to be better established and more trials are needed to assess the clinical implications of these findings. Dr. Pedersen presented some preliminary data comparing once- daily administration of ciclesonide (320 µg PM) with budesonide (400 µg PM) and stated that ciclesonide appears to be slightly more effective and has a slightly faster onset of action compared to budesonide.

Concluding remarks
Dr. Pedersen ended the symposium by telling the audience that different inhaled corticosteroids show markedly different pharmacokinetic properties, suggesting different potential outcomes for each of these medications. While all inhaled steroids show clinical effects when dosed once-daily, more studies are needed to assess whether the clinical effects (in a variety of asthma outcomes) are similar to those seen with more frequent dosing.