Approaching Asthma Therapy From Real World Solutions

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians in Orlando, Florida, three leading asthma researchers discussed recent developments in the use of inhaled cortico-steroids for the treatment of asthma.

This program was supported by an unrestricted educational grant from Aventis Pharmaceuticals, Inc. and ALTANA Pharma.

Overview of Non-Infectious Precipitants to Asthma Exacerbations: What Causes Your Patients to Wheeze?

Monica Kraft, MD, FCCP, Associate Professor of Medicine at the University of Colorado Health Science Center and Director of the Felt Laboratory for Adult Asthma Research, National Jewish Medical and Research Center in Denver, CO, began the symposium by saying “I don’t have to tell this group that it is well known that infections exacerbate asthma.” In particular, etiological studies with Mycoplasma pneumonia and Chlamydia pneumonia have shown that these organisms may play an important role in the development or exacerbation of asthma in some patients. For example, Drs. Hahn and McDonald at the University of Wisconsin (Ann Allergy Asthma Immunol. 1998;81:339-344) studied 163 adults with acute wheezing or chronic asthma over a nine-year period in an outpatient clinic and of these patients, 20 were diagnosed with C. pneumoniae. Of these 20 patients, 10 already had asthma and of the remaining 10 patients, 6 developed asthma. In addition, a study by Emre et al. (J Infect Dis. 1995; 172: 265-267) examined the role of chlamydia infection in asthmatic children by grouping children into 4 categories [1. culture-positive asthmatics (n = 14); 2. culture positive with a history of pneumonia but no history of asthma (n = 11); 3. culture negative asthmatics (n = 11); 4. control (n = 9)]. Only the cultural positive asthmatic group was found to have a high prevalence (12 of 14) who manifested C. pneumoniae IgE (Table 1).

In regard to Mycoplasma pneumoniae, Seggev and colleagues (J Infect Dis. 1995;172:265-267) performed serology on 95 asthma patients and found that 20 of the patients (21%) exhibited IgM specific antibodies against M. pneumoniae suggesting acute infection. Animal models have also suggested a link between mycoplasma infection and asthma but Dr. Kraft stated her interest in the correlation between asthma and M. pneumoniae stemmed from case studies. For example, a 22-year-old woman with a diagnosis of asthma since childhood was found to have M. pneumoniae in her airways. The patient was treated with clarithromycin and each time the patient was taken off the clarithromycin, her asthma got significantly worse. These and other case studies led Dr. Kraft and colleagues to speculate that if M. pneumoniae and C. pneumoniae are causal factors in chronic asthma in certain individuals, then treatment with clarithromycin, a macrolide with known activity against mycoplasma and chlamydia species as well as anti-inflammatory effects, would improve asthma. To test this hypothesis, Dr. Kraft was involved in a trial examining 55 asthmatic patients and 20 controls. Of the 55 asthmatics, 23 showed PCR evidence of M. pneumoniae and 7 were positive for C. pneumoniae. While the patients with C. pneumoniae failed to improve following clarithromycin, there was improvement (increased FEV1) in the M. pneumoniae (PCR positive) patients.

It has also been hypothesized that M. pneumoniae may affect the airway’s response to neurogenic inflammation. An examination of substance P receptors (neurokinin-1) found them to be much higher in PCR positive (M. pneumoniae) asthmatics. Furthermore, the changes in these receptors may explain the observation that PCR positive asthmatics produce more TGF-beta compared to the PCR negative asthmatics. Dr. Kraft said, “there may be some differences in how these PCR positive and negative asthmatics handle neurogenic inflammation.”

In conclusion, Dr. Kraft stated that M. pneumoniae and C. pneumoniae are present in the airways of patients with asthma. In patients that are PCR positive for M. pneumoniae, treatment with clarithromycin improves FEV1 and preliminary data indicates that mycoplasma increases sensitivity to substance P.

Behind the Safety and Efficacy of Inhaled Steroids: Pharmacokinetic/Pharmacodynamic Principles

“I would like to present my personal view of what a really good inhaled steroid should look like,” began Guenther Hochhaus, PhD, Professor of Pharmaceutics at the University of Florida, College of Pharmacy in Gainesville, FL. The first inhaled steroid on the market was beclomethasone dipropionate and it was followed by triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate. Two inhaled steroids in development are mometasone furoate and ciclesonide. With the number of inhaled steroids available, it is difficult to determine which is best, but Dr. Hochhaus uses PK/PD models to illustrate some of the differences between these medications and what properties the ‘ideal’ inhaled steroid should have.

Pharmacokinetics/Pharmacodynamics (PK/PD)
“Pharmacokinetics deals with the relationship between the concentrations of a drug in blood and time,” stated Dr. Hochhaus, adding “pharmacodynamics deals with the relationships between the concentration of the drug at the site of action, and the extend of the observed pharmacological effect.” Together, a PK/PD relationship can be useful in examining the change of an effect (i.e., desired pulmonary effect and/or undesired systemic side effects) versus time.

When a steroid is inhaled, generally, 10-60% of the medication will reach the lung while the rest is swallowed. The drug deposited in the lung is able to induce the desired pulmonary effect. Furthermore, once the steroid in the lung has its anti-asthmatic effect, it can still be absorbed systemically. Thus this fraction together with the amount of drug that is swallowed and orally absorbed will be able to induce systemic side effects. The extent of systemic side effects will be less if little drug is entering the systemic circulation or if the drug is being eliminated efficiently. “So we need to select an inhaled steroid that once it’s been absorbed systemically is being removed efficiently,” stated Dr. Hochhaus.

Receptor Binding
Dr. Hochhaus said that fluticasone propionate and budesonide have greater receptor affinities than the other inhaled steroids such as triamcinolone acetonide or flunisilide. “But is that an advantage?” asked Dr. Hochhaus, adding, “if we simulate those kinds of scenarios with this PK/PD model that I just described, what actually turns out is that the difference in receptor binding affinity can be counteracted by just selecting the right dose.” In other words, the receptor affinity is a secondary parameter and the pharmacokinetic properties, the properties that describe the fate of the drug in the body, are probably more important to achieving the highest degree of pulmonary selectivity.

Oral Bioavailability
Oral bioavailability determines how much of the swallowed drug enters the systemic circulation through GI absorption. The ideal inhaled steroid would have an oral bioavailability of zero. That has not been fully achieved but some of the newer steroids (ciclesonide, mometasone furoate and fluticasone) do have very low oral bioavailability (< 1%) compared to the other steroids (Table 1).

Half-Life (t1/2), Clearance and Volume of Distribution
PK/PD relationships were also used by Dr. Hochhaus to discuss whether long half-lives of inhaled steroids are necessarily bad. From a kinetic point of view, the half-life is determined by two parameters: the systemic clearance and the volume of distribution. The higher the systemic clearance the more active the body is able to eliminate the drug once it has been absorbed and this improves targeting. The second parameter, the volume of distribution quantifies distribution. The newer inhaled steroids show relatively high volume of distributions because they are very lipophilic and concentrate in tissue. Using a PK/PD model, however, high volume of distributions leads to long half-lives yet no difference in pulmonary selectivity. As such, t1/2 is not a valid parameter to determine if an inhaled steroid is efficient.

Protein Binding
PK/PD relationships can also be influenced by protein binding which is the degree to which a drug binds to a blood component such as albumin. Dr. Hochhaus stated that protein binding differs significantly among the inhaled steroids with the newer steroids (mometasone furoate or ciclesonide) having much smaller percentage of drug present in the blood that is free (i.e., active form).

Pulmonary Residence Time
Pulmonary residence time is the time that a drug molecule stays in the lung. To illustrate the importance of this parameter, Dr. Hochhaus showed PK/PD models of three steroids, one drug that dissolves very quickly in the lung, one that dissolves at an intermediate rate and one that dissolves very slowly. Using this model Dr. Hochhaus said, “what you see is that there seems to be an optimum residence time where we will see most of the targeting occurring.” Among the steroids, pulmonary residence time varies greatly but can be influenced by a combination of steroid kinetic properties and drug delivery systems. For example, drugs can be placed in liposomes. Another example to increase pulmonary residence time is to use medications that interact with lung enzymes to create a form that is retained longer in the cell. This happens with budesonide and ciclesonide where the drug enters the pulmonary cells and enzymes convert the glucocorticoids into lipophilic esters that are trapped in the cell and cannot interact with the receptor. Slowly, the ester is cleaved and the drug can interact again with the glucocorticoid receptors in the lung.

Concluding Remarks

Dr. Hochhaus ended his presentation by stating that the ideal corticosteroid should produce high targeting if it has:

• prolonged residence time
• low oral bioavailability
• high systemic clearance

Improving Adherence with Asthma Therapy

“It comes as no surprise that many patients do not do what we’ve asked them,” stated Frederick S. Wamboldt, MD, Professor of Medicine and Head of the Division of Psychosocial Medicine at the National Jewish Medical and Research Center and Professor of Psychiatry at the University of Colorado Health Sciences Center in Denver, CO. To introduce the topic of improving adherence to asthma therapy, Dr.Wamboldt told the audience that in addition to talking about lung inflammation and airway remodeling he would talk about the relationship between ‘relationship inflammation’ and ‘family remodeling’. If a child has asthma, key relationships in the family may become inflamed and their reactions to events and their roles in the family hierarchy may be remodeled. How the family copes with relationship inflammation has an effect on treatment adherence.

To introduce some of the data available on treatment adherence, Dr. Wamboldt discussed adherence data generated over the course of a year using devices attached to the inhaler that recorded dosages of inhaled anti-inflammatory medication taken each day. Generally, it was found that only 21-23% of patients adhered to treatment most of the time (i.e., took > 75% of their doses across a year of observation), 29% adhered more than half the time (50-74%), 21-32% adhered some of the time (25-49%), and 16-29% adhered poorly (< 25%).

In a follow-up of children previously hospitalized at National Jewish who had very poor adherence at admission, these patients had almost a two-fold increase in rehospitalization rates and/or a three-fold increase in catastrophic asthma events after discharge. “I think what we really know from the adherence research to date is that people who take almost no steroids have most of our adverse outcomes,” stated Dr. Wamboldt, adding however, “we have really no data that I know of that suggests people who take all of their medicines are really better in the real world than people who take half of their prescribed medicine.”

Family Effects
Are families who are adherent with asthma medications also more likely to adhere to home environmental recommendation such as not smoking and avoiding pets with fur and feathers? Dr. Wamboldt’s research suggests “no,” the prevalence rates of household smoking and ownership of allergenic pets is no different in families with children with asthma than the general population and the presence of a smoker in the house or a pet are not correlated with adherence (J Pediatr. 2002;141:109-115).

To better understand the influence of family dynamics on treatment adherence, Dr. Wamboldt and colleagues developed a study to quantify the patient’s and family’s knowledge of asthma, their relations, and their advice. The ‘relationship inflammation’ score measured the strength of the parent-child relationship and the ‘advice quality’ score was a measurement based on how family members provided advice about dealing with asthma in real world situations. Surprisingly, asthma knowledge scores were neither related to adherence with inhaled medications nor any of the asthma outcomes in this study (JACI. 2003; 111:498-502). More important factors that predicted adherence were the race of the child, the age of the child, the relationship inflammation score, and the advice quality score (Am J Respir Crit Care Med. 2002;165:A197). Summariz-ing the data, Dr. Wamboldt said, “I think we do have some evidence that various family processes affect treatment adherence although there’s not just one type of good or bad citizen family out there.”

Dr. Wamboldt finished his presentation with a brief discussion on obesity and asthma. Obesity is very prevalent in asthma patients, likely due to the sedentary lifestyle these children develop to avoid asthmatic attacks. While this might be a good short-term adaptive measure, long- term consequences clearly are problematic.

New Therapies: Impacting Patient Care

The final presentation of the symposium returned Dr. Monica Kraft to the podium to discuss new therapies for asthma. At present, inhaled steroids are the first- line therapy for mild, moderate, and severe persistent asthma. Inhaled steroids may also be combined with a long-acting beta agonist if symptoms persist. Second- or third-line therapies also include leukotriene modifiers. After introducing the list of inhaled steroids available, Dr. Kraft then asked, “is there variability in steroid response and if so, are there predictors of steroid responsiveness?” To answer this question, Dr. Kraft discussed some research she has been involved with at the Asthma Clinical Research Network that was interested in the variability of drug responsiveness with steroids. Most studies compare two or three steroids so the Asthma Clinical Research Network developed the DICE (Dose of Inhaled Steroid Equi-systemic) study to examine the cortisol suppression dose response curve for six inhaled steroids and were able to establish doses that provide 10%, 30%, 40%, and 50% change in FEV1. Following this study, the MICE (Measure of Inhaled Corticosteroid Efficacy) study was developed to compare benefit versus systemic effect of representative inhaled steroid delivery device combinations, identify efficacy tests to use in future trials, determine the degree of variability in certain efficacy measures, and define methodology for therapeutic index. Preliminary results from this study were given by Dr. Kraft comparing beclomethasone and fluticasone metered dose inhalers and showed that “both drugs showed their maximal effects (FEV1) at fairly low doses. Closer examination found that approximately one-third of the patients demonstrated a 15% increase in FEV1, one-third improved between 5% and 15%, and one-third improved less than 5%. Further analysis found that the ‘steroid responders’ generally had other factors such as sputum eosinophils (>3%), a bronchodilator response to albuterol of about 15% or more, and an asthma duration of less than 10 years. “If you had those three characteristics, you were much more likely to fall into the steroid responder group,” said Dr. Kraft, adding “and if you didn’t have any of those predictors, you fell into what we call the non-responders and if you had maybe one of the three you fell into this middle group.”

Other Treatment Options
Among the new treatment options that will be available, Dr. Kraft first discussed HFA meter dose inhalers (MDI) which contain smaller particles that allow medication to reach distal regions of the lung. Two HFA-MDI inhalers are ciclesonide and flunisolide.

Other treatment options in development include IL-5 antibodies, IL-12 antibodies, PDE-4 inhibitors, and omalizumab. To date, none of these compounds have proven to be safe and effective for the treatment of asthma but studies with omalizumab do show promise in some patients but further studies are needed.

Concluding Remarks
Dr. Kraft ended her presentation by stating, “the equi-systemic effect of corticosteroids can be compared using cortisol suppression as a measure of steroid effect.” Furthermore, the HFA-MDI inhaled steroids offer the ability to treat inflammation in the distal lung with less systemic cortisol suppression. Among the new treatment options available, the cytokine modulation therapies have been disappointing but the anti-IgE, omalizumab, shows some promise in moderate to severe atopic asthmatics.