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New Insights into Inhaled Corticosteroids

Inhaled Steroid Pharmacokinetics

“What I’m going to talk about is inhaled steroid pharmacokinetics and mechanisms of action,” began Stanley Szefler MD, professor of Pediatrics and Pharmacology at National Jewish and the University of Colorado in Denver, Colorado, adding “and the underlying theme of my talk will be: is there room for improvement?” When comparing inhaled steroids, there are several methods available, inducing pulmonary function measures, hyperresponsiveness, exacerabation, symptoms, asthma progression, inflammation, pharmacokinetics, pharmacodynamics, and so forth.

The best population to study the efficacy of an inhaled steroid is patients with moderate to severe asthma. Furthermore, when comparing inhaled steroids, both systemic and beneficial effects can be studied. One method of doing this is “to identify equivalent doses that would provide beneficial effects and then look at relative systemic effects or vice versa,” said Dr. Szefler, adding, “and what we chose to do was look at systemic effects for the various inhaled steroids available, get different levels of cortisol suppression and from our studies we found overnight serial plasma cortisol suppression to be the best measure.” In the first study using this method(Am J Respir Crit Care Med 2002;165:1377-1383), several steroids and delivery devices were studied and they found that the metered dose inhaler (MDI) with fluticasone was the most effective in suppressing cortisol and the dry powder preparatons were the least effective. In a second study, Dr. Szefler and colleagues (J Allergy Clin Immunol 2002;109:410-418) sought to identify a battery of efficacy tests to compare the two most effective treatments from the previous study, namely fluticasone MDI and beclomethasone MDI. “What we found again to our surprise was that the maximal effect was already achieved in terms of this FEV1 parameter at the lowest dose,” said Dr. Szefler, adding, “there was little or actually no improvement by going to the medium or the high dose, or switching the delivery device.” A similar pattern was observed when examining efficacy using methacholine PC20. Dr. Szefler hopes this study design will be used by the FDA to select low, medium and high doses to test for efficacy and safety components.

The ideal inhaled steroid?
According to Dr. Szefler, “one might characterize the ideal inhaled steroid as having high receptor binding, greater pulmonary deposition, prolonged residence time in the lung, low oral bioavailability to really minimize the systemic effect that comes from GI absorption.” Several other factors must also be addressed to balance the efficacy and safety of a given steroid (see PF/PD presentation by Dr. Hochhaus). Dr. Szefler said “if we look at a drug like ciclesonide, it has some features that may be favorable in terms of its receptor binding, in terms of targeted inhalation, in terms of the pharmacokinetics and pharmacodynamics that may lend itself to being a more potent inhaled steroid,” adding, however, that comparisons of ciclesonide with other inhaled corticsterois are needed.

Inhaled Corticosteroids: Potency vs. Efficacy – What Really Matters?

Inhaled corticosteroids have proven to be effective and safer than systemically administered corticosteroids. However, the fear of inhaled corticosteroids to induce systemic adverse events such as growth retardation in children and changes in bone density remains a discussion point in the medical community, according to Guenther Hochhaus, PhD, Professor in the Department of Pharmaceutics at the University of Florida in Gainesville, Florida. “The question is how can we further maximize this therapy and continue to reduce potential side effects that we might see occasionally in the treatment with inhaled glucocorticoids? ” asked Dr. Hochhaus. Pharmacokinetic/pharmacodynamic (PK/PD) correlations can be used to assess which properties of an inhaled corticosteroid (i.e., beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate) or corticosteroid in development such as mometasone furoate or ciclesonide are important for treatment efficacy and safety.

Dr. Hochhaus introduced the topic of PK/PD studies by stating that pharmacokinetics describe the relationship between drug concentration and time while pharmacodynamics describe the relationship between the effect and the drug concentration. Combining these two relationships lead to PK-PD correlations as the relationship between effect and time. Using these PK/PD correlations, models can be developed for inhaled steroids and “relationships between the receptor occupancy in the lung , as a surrogate marker of the pulmonary effects, and the systemic receptor occupancy, as a surrogate marker of the systemic side effects, can be used to estimate efficacy (steroids to lungs) and safety (steroids to body) and quantify pulmonary selectivity. “And a good inhaled steroid with high pulmonary selectivity will show a distinct difference between systemic and pulmonary receptor occupancy profiles,” stated Dr. Hochhaus.

“If we talk about assessing the importance of pharmacodynamic differences among the inhaled glucocorticoids at the site of action, then a relevant parameter for comparison would be the receptor binding affinity,” said Dr. Hochhaus. However, as receptors in the lung and systemic organs are very similar, drugs with high receptor binding affinities will be both highly active at the receptors in the lung (i.e., target site) and highly active at the receptor in other areas (i.e., side effects). It is therefore that the receptor binding affinity of a given corticosteroid should be considered as a secondary factor, according to Dr. Hochhaus, as drugs with different receptor binding affinity (and otherwise identical pharmacokinetic properties) will induce the same pulmonary selectivity as long as differences in receptor binding affinity are accounted for by adjusting the dose.

PK/PD correlations
“The most important properties for an inhaled glucocorticoid are its pharmacokinetic properties,” stated Dr. Hochhaus and there are several different components that are important. First among them is bioavailability. Systemic bioavailability of inhaled steroid can be through oral absorption and/or through the lung. To illustrate, Dr. Hochhaus discussed a study by Dr. Thorsson et al. who used the charcoal technique to differentiate between drugs that enters the systemic circulation through the lung and through the GI tract. Using this technique it was demonstrated that using a turbuhaler, 32% of the delivered dose drug found systemically came from the lung compared to 6% from the GI tract. In the metered dose inhaler, the percentages are 15% through the lung and 11% from the GI tract (Eur Respir J 1994; 7:1839-1844). These results indicated that different delivery devices might differ in the pulmonary deposition and the amount of drug available for systemic absorption through the GI tract.

Using a simulation program, Dr. Hochhaus showed the audience that low oral bioavailability of an inhaled steroid (i.e., as shown for fluticasone propionate, ciclesonide) is beneficial for lung targeting. Dr. Hochhaus stated that one benchmark for developing new inhaled steroids is an oral bioavailability less than 1%.

Another parameter is the drug’s half-life which is dependent on systemic clearance and volume of distribution. Using simulations, Dr. Hochhaus illustrated that higher clearance translates into greater targeting. Dr. Hochhaus said “if one wants to make a better glucocorticoid with respect to clearance, one actually needs to find glucocorticoids that are being metabolized outside of the liver and that is not an easy task to identify.” The other factor that determines half-life is volume of distribution and Dr. Hochhaus showed the audience that although a larger volume of distribution means a longer half-life, a larger volume of distribution is not compromising lung selectivity.

Protein binding is also important. The lowest protein binding is found with triamcinolone acetonide at approximately 80% (i.e., 20% free) while very high protein binding is observed with the newer glucocorticoids, mometasone furoate and ciclesonide. In general, the higher the protein binding for drugs with high clearance, the lower the systemic side effects. However, future studies need to evaluate whether a more pronounced tissue and protein binding also decreases the pulmonary efficacy.

“Another very important factor is the pharmacokinetic fate of the inhaled steroid in the lung,” said Dr. Hochhaus, referring to the pulmonary residence time or the amount of time an inhaled steroid stays in the lung. Using simulations, Dr. Hochhaus showed the audience that a drug that is absorbed quickly will not stay in the lung long enough to provide targeting while a drug that stays in the lung for up to 5 hours can have a high level of targeting. Pulmonary residence time, though, does have its limitations since mucociliary clearance can occur if a drug stays in the lung too long and glucocorticoids that dissolve too slowly will not be able provide pulmonary targeting. “One parameter that we could use to quantify the residence time of the drug is called the mean absorption time that can be calculated quite easily from pharmacokinetic studies if we have intravenous as well as inhalation kinetics available,” said Dr. Hochhaus. Further-more, there are several new approaches in development that may optimize the pulmonary residence time of an inhaled glucocorticoid.These approaches involve the use of steroids which remain trapped in pulmonary cells for a prolonged period of time (as shown for a fraction of pulmonary deposited budesonide), the use of slow- release dosage forms such as pulmonary microspheres or slow dissolving lipophilic drugs or prodrugs (e.g., ciclesonide) which also “have the potential to stay in the lung for a longer period of time,”stated Dr. Hochhaus.

Whether such prodrugs prove to be safe and effective remains to be fully established but the possibility of these drugs having prolonged residence time in the lung is promising.

Concluding Remarks
The three main factors for developing the ideal corticosteroid are prolonged residence time in the lung, very low oral bioavailability, and very high systemic clearance. PK/PD studies can help determine these criteria and are useful tools for developing and comparing inhaled corticosteroids.

Approaches to Asthma Therapy: The Future is Now

Sally E. Wenzel, MD, Professor of Medicine at National Jewish Medical Center in Denver, CO began her presentation by asking “Do we really need better or newer approaches to the treatment of asthma?” The answer is yes.

The ‘ideal’ corticosteroid
Currently, we are not doing a good enough job in treating severe asthma, according to Dr. Wenzel. In the famous CAMP (Childhood Asthma Management Program) study (NEJM 2000; 343:1054-1063) it was shown that after 4 years of treatment with budesonide, medocromil, or placebo none of the treatments had any impact on FEV1. In order to improve these outcomes, Dr. Wenzel expanded on Drs. Szefler’s and Hochhaus’ presentations with a list of the parameters necessary for the ‘ideal’ corticosteroid (Table 1).

While all of these parameters are important, Dr. Wenzel focused on the importance of the delivery of drug to the small airways and the parenchyma. The current available corticosteroids are delivered primarily to the large airways. In a comparison of fluticasone DPI and fluticasone MDI, the MDI method has a much smaller particle size allowing for deposit of the drug into the smaller airways and was more effective. Fortunately, “there are in development new delivery systems and propellants which enhance the delivery of the drugs to the small airways,” said Dr. Wenzel. Among them is HFA beclomethasome. “This system was developed primarily because of the need to eliminate chlorofluorocarbons using a different propellant,” said Dr. Wenzel, adding, “but the HFA propellant with the steroid, put the steroid in solution, and that produced a system with a very small particle size which was able to be delivered to the small airway.” While data with this drug is limited, HFA beclomethasone has increased deposition in the lung and is more effective that older CFC preparations (Eur Respir J 1998;12:1346-1353; J Allergy Clin Immunol 1999;104:1215-1222; J Allergy Clin Immunol 1999; 104:S258-S267).

Another important parameter for developing the ideal corticosteroid is the quality of the corticosteroid. Dr. Wenzel used the newer inhaled corticosteroid, ciclesonide, as an example of improved quality. Among the advantages of ciclesonide is that is is a prodrug that is only activated at the target site. “The activation specifically in the lung should minimize the systemic adverse effects as well as minimize those kind of nagging oral-pharyngeal side effects that we see with many of the currently available inhaled corticosteroids,” said Dr. Wenzel.

Combination therapy
Another area that can improve asthma therapy is the use of combination products such as a bronchodilator and an anti-inflammatory agent. The only combination product currently in use is the inhaled steroid plus a beta agonist. “It’s likely to be more effective than doubling the dose of inhaled steroids on the basis of several studies that have been published over the years,” said Dr. Wenzel, adding “and I think it is possible that the addition of a bronchodilator leads to a better adherence.”

Preventive Therapy
The scientific rationale for preventive therapy is to manipulate the TH-1 and TH-2 pathways at an early stage in a child’s life. “You can perhaps increase the good TH-2 response or shift the balance of TH-1 and TH-2 in the direction of TH-1 and away from TH-2 early in life,” said Dr. Wenzel. While data is limited, studies involving children and cat exposure found that children exposed to high levels of cat allergens developed more protective IgG concentrations (Lancet 2001;357:752-756). Dr. Wenzel joked, “if you’re going to have a cat in your house, you shouldn’t have one cat in your house, you should have eight or ten cats in your house and that may actually protect you from the development of allergies and asthma later on in life.”

Another preventive approach is exemplified in a recent study by Dr. Wenzel and colleagues (Am J Med 2002; 112; 627-633), who gave children with bronchopulmonary dysplasia a prophylactic dose of RSV immune globulin to prevent a “second hit” that could stimulate asthma. These children were followed for 10 years and it was observed that they had significantly better lung function and fewer lower respiratory tract infections than the control group.

Targeting specific inflammatory pathways
There is a lot of interest in the TH-2 pathway as an important factor in the development and propagation of asthma. As such, there are several drugs in development that may inhibit the TH-2 pathway, including anti-IgE, antibodies to IL-5, soluble IL-4, and VLA-4 antibodies. Of these, the anti-IgE is showing the most promise and has been shown to decrease hospitalization in severe asthma patients. Another promising approach involves blocking IL-4. In a study by Dr. Borish et al (Am J Resp Crit Care Med 1999;160:1816-1823), patients were given soluble IL-4 to block naturally occurring IL-4 function and it was found that soluble IL-4 (1500 µg) reduced the need for b2 agonists compared to placebo or low dose soluble IL-4 (500 µg). Studies with anti-IL-5 have been designed to reduce eosinophils but they have not been effective in reducing asthma systems (Lancet 2000;356:2144-2148). Finally, a study designed to improve the TH-2/TH-1 balance by adding IL-12 have not proven to be successful (Lancet 2000;356:2149-2153).

Concluding remarks
Although there have been great advancement in our understanding of asthma and its treatment, there is still a need for further improvements. Future treatment regimens can improve outcomes if they are designed to treat the pathobiology of asthma as well as the inflammation associated with the various types of asthma.


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