Destination: Distal Lung –Reaching a New Frontier in Asthma Management

At an industry-sponsored symposium held in conjunction with the American College of Allergy, Asthma and Immunology 2003 Annual Meeting, three leaders in the treatment of asthma presented a review of current information and the newest clinical data regarding the deposition and distribution of medications into the distal lung. Specifically, the importance of enhancing passage of inhaled corticosteroids through the airways and arriving at new solutions for managing asthma.

This program was supported by an unrestricted educational grant from Forest Laboratories, Inc.

Embarking on a New Understanding of the Pathophysiology of Asthma

Often overlooked in treating asthma is the presence of distal lung inflammation and its influence on response to medication. Physicians may find themselves asking “is that a reason why inhaled steroids do not normalize hyper-responsiveness?”

Elizabeth Wagner and colleagues measured peripheral airway resistance (PAR) by introducing gas at a certain flow via a bronchoscope in a group of mild asthmatics and one group of normal patients. In normal subjects, the slope of the line of resistance was low and consistent. The asthmatics had a significant elevation in PAR despite forced expiratory volume in 1 second (FEV₁) measurements in excess of 90% of predicted (Wagner E, et al. Am Rev Resp Dis. 1990;141:584).

“They also instilled histamine into the catheter and measured PAR,” said Monica Kraft, MD, Associate Professor in the Division of Pulmonary Sciences and Critical Care at the University of Colorado Health Sciences Center. “The normals had insignificant changes in resistance when compared with asthmatics, suggesting the smaller airways did manifest signs consistent with hyper-responsiveness.”

Kraft’s group studied PAR in patients with nocturnal asthma (NA) and controls. They were assessed at four in the afternoon and four in the morning. Patients were told to hold their breath in order to measure the decay of pressure after the flow of gas was stopped. In the normal group, it decayed to near zero while staying elevated in those with asthma (Kraft M, et al. Am J Respir Crit Care Med. 2001:163: 1551).

“When we stop the flow, it should diffuse into collateral channels and escape,” said Dr. Kraft. “This did not seem to be happening in those with
asthma.”

The study revealed a significant increase in PAR for the nocturnal group and a trend toward slightly higher resistance at 4 a.m. when compared to the
afternoon. This latter finding may be an artifact of relatively small sample size.

Despite a small sample size, significant differences were seen when closing pressures were recorded. Those with NA had much higher closing pressures at night than during the day. Dr. Kraft hypothesized that this may be related to airway inflammation and edema closing channels of communication and therefore preventing escape.

“Now that I’ve shown some physiology, I would like to add a little bit about pathology,” said Dr. Kraft. “We know that inhaled corticosteroids (ICS) work well in the proximal airways and we also know that peripheral inflammation exists in small airways.”

A study by Hamid, et al. looked at asthmatic patients and controls undergoing surgery, allowing for larger lung tissue specimens than would be available using bronchoscopy. They looked at a number of different inflammatory cells in the large and small airways and found that asthmatics had more T-cells and eosinophils suggesting that inflammation is distributed throughout the bronchial tree (Hamid Q, et al. JACI. 1997;100:74).

A second study looked at large airway biopsies taken at 4 a.m. and 4 p.m. There were no differences in T-cells or eosinophils, leading them to conclude that inflammation was not driving these changes in lung function (MacKay TW, et al. Thorax. 1994;49:257).

“We wondered if this was a function of needing to look farther in the lung to see what is going on,” said Dr. Kraft.

Kraft and colleagues looked at large airways using an endobronchial biopsy and alveolar tissues via transbronchial biopsy. These studies were done in the afternoon and early morning hours and both nocturnal and non-nocturnal patients were enrolled.

They found no differences in the numbers of eosinophils in the afternoon testing. However, at four in the morning, the eosinophil counts were significantly higher in the NA, but only in the distal alveolar tissue. There was no relationship between the fall in large airway FEV₁ versus large airway eosinophils. In contrast, there were significantly more eosinophils seen in the alveolar tissue of nocturnal asthmatics asthe FEV₁ fell. When comparing 4 a.m. FEV₁ and CD4 cells in the proximal airways, no relationship existed. Once again, the lower the FEV₁, the more T-cells were found in the distal lung. (Kraft M, et al. Am J. Resp Crit Care Med. 1999;159:228).

“From a physiologic point of view, these cells appear to have an impact on lung function,” said Dr. Kraft.

Parenchymal inflammation in the alveolar tissue may be important. Hauber and colleagues looked at inflammation in both the larger and smaller airways emphasizing macrophages, basophils, eosinophils, neutrophils and lymphocytes. They found similar numbers of cells present in both the proximal and distal lung (Hauber P, et al. JACI. 2003; 112:58).

“When these patients were given hydrofluoroalkane (HFA) flunisolide, they responded in a positive way reducing inflammation in both the peripheral and central airways,” noted Dr. Kraft. “This impact on both compartments of the lung is potentially a nice advantage.”

Looking at changes in the inner and outer walls of airways may explain some of the changes in recoil.

Carroll and others compared autopsy results from patients in a control group with those who died from asthma and a third group of patients with asthma that died of other causes. When focusing on the larger airways, many of the changes they saw were limited to fatal asthmatics. However, when attention was directed toward the smaller airways, both asthmatic groups had similar changes that varied from the control group. They hypothesized that the changes in the smaller airways may be happening sooner (Carroll N, et al. Am Rev Respir Dis. 1993;147:405).

“Hopefully I have got you thinking about distal lung inflammation in asthma,” she said. “While we see changes, we do not yet know if they are meaningful to physiology and ultimately the patient. I would argue that treatment strategies should consider this compartment.”

Enhancing ICS Passage Through the Airways

Delivering aerosol medications to a patient is a challenge. The aerosols have to be of a specific size to be inhaled and deposited in the lung. The inhalation technique is important, with different inspiratory volumes and flow rates needed for different types of medication. Bronchoconstriction needs to be minimized to avoid depositing medication proximal to areas of constriction and reducing the likelihood of penetrating into the distal lung.

“The geometry of the lung is such that the airways are folded back on each other to accommodate the volume of the chest cavity,” explained Myrna Dolovich, P. Eng., Associate Professor of Medicine and Radiology at St. Joseph Hospital in Hamilton, Ontario. “This layering effect makes the measurement of deposition in different generations of airways difficult to determine.”

The Montreal Protocol called for changes in the propellants used to drive the drug out of pressurized containers and into the lungs. There were three main strategies used in the changeover from chlorofluorocarbons (CFC) to hydrofluoroalkanes (HFA).

The first was to change the propellant only, thus moving from one kind of suspension to another. This had the advantage of allowing the aerosol properties to remain the same, as well as the behavior of the aerosol in the lung. Fluticasone dipropionate HFA is one example of this type of formulation.
A second strategy was reformulation from a suspension to a solution. Aerosol solutions produce finer aerosols and should, presumably, have better penetration into the distal lung. Flunisolide HFA is an example of this type of reformulation.

The third option changed both the formulation and delivery system by adding an additional inhalation device (i.e., spacer) to the mouthpiece actuator. This feature lessens the need for coordinating the actuation with inhalation.

There can be as much as a six-fold difference in the median diameter of corticosteroid particles from different types of inhalers. Studies indicate the peak of the distribution curve is around 3-microns with deposition partitioned approximately equally between the airways and the parenchyma. HFA formulations deliver finer droplets, from a median diameter of 3-microns to as fine as 1-micron.

Particle size plays an important role when discussing distribution and deposition of aerosols into the lung. Prof. Dolovich pointed out that pressurized aerosols or mists are not the only delivery systems available for ICS aerosols. Other choices are dry powder inhalers (DPIs) and nebulizers. The aerosols from these inhalers also have different particle size characteristics.

Initial size may not be the final size of the deposited material. A Canadian study by Mitchell and co-workers using ventilators and a 1-micron median
diameter HFA inhaled corticosteroid characterized these particles under high humidity conditions. They found that in humid conditions similar to those in the lung, the extra-fine particles grew to nearly 3-microns median diameter (Mitchell JP, et al. Resp Care. 2003; 48:1025).

“Thus, there can be changes in extra fine aerosol size when inhaled into the lung,” said Prof. Dolovich. “Stable 1-micron aerosols act like gases with minimum sedimentation and diffusion rates and can be targeted to the distal airway. However 3-micron aerosols behave differently and deposit on more proximal airways.”

However, in order for all of this to occur, laminar flow on inhalation is desired as well as open airways. Proper inhalation of medication means ventilation distributes the drug and the particles impact minimally at bifurcations.

To illustrate this, Prof. Dolovich pointed to the results of a positron emission tomography (PET) scan done in her laboratory. When bronchoconstriction in an asthmatic was induced with methacholine, there was a much higher rate of particle impaction in the central airways, even with 1-micron particles, preventing drug delivery to the peripheral lung. Similar findings have been seen in studies using other types of tests.

“With 1-micron particles, we have seen rapid uptake from the periphery of the lung that largely isn’t seen in the proximal airways when they are constricted,” she said. “Thus there may be a differential absorption of drug from different regions of the lung. The optimal deposition of a drug is where the receptors and the disease are in the lung.”

What are the differences in deposition of medications in the lungs when comparing 3- micron versus 1-micron aerosols?

Prof. Dolovich and others compared QVAR (3M Pharma, St. Paul, MN), a 1-micron HFA aerosol solution of beclomethasone to 3-micron CFC Beclovent, a suspension aerosol of beclomethasone diproprionate (GSK, RTP, NC). Subjects were given two puffs of albuterol to maximize delivery of the smaller-sized particles to the lung and Xenon scans were done prior to delivery of a radioactive tagged formulation of the steroids. They found roughly a three-fold difference in terms of total drug delivered with approximately 18% for Beclovent v. 50% for QVAR (Dolovich M, et al. AJRCCM. 2000:161:A33). (Figure 1)

The next question is the amount of drug that reaches the peripheral lung. Again when comparing QVAR to Beclovent, one sees an increase in total dose delivered throughout the lung for the finer aerosol product; that is an increased dose to both the lung periphery and the central airways for QVAR.

To say with certainty where the 1-micron medication is deposited in the lung requires a 3-dimensional imaging study. To address these issues, two
studies using single photon emission tomography (SPECT) studies have been undertaken using a flunisolide tracer.

In regions A, B, and C (corresponding to the central, middle, and peripheral areas of the lung), deposition from the extra-fine HFA formulation of flunisolide was found to be 18%, 40% and 43%. For the larger particle CFC formulation, the amounts were 23%, 38% and 40% respectively. Thus, in these mild asthmatic subjects, there was a slight increase in the peripheral dose and less in the central region for QVAR (Newman SP, et al. American Academy of Allergy, Asthma and Immunology Meeting, 2003. Denver, CO).

The second SPECT study in healthy volunteers compared HFA flunisolide and CFC fluticasone. Fifty-four percent (54%) of the HFA medication was
deposited throughout the entire lung compared to 18% of the CFC fluticasone dose. However, the peripheral-to-central deposition ratio for HFA fluticasone was the same as for the CFC flunisolide formulation (Newman S, et al. American College of Allergy and Asthma Meeting. 2003, New Orleans [abstract]).

“We have HFA solution cortico-steroids on the market that are finer and tend to deliver drugs more peripherally than their original CFC formulations,” said Prof. Dolovich. “The HFA solution corticosteroids also deliver about 3 to 4 times more total drug to the lung than the CFC suspension formulations.”

Arriving at New Solutions for Managing Asthma

The next step, according to Jonathan Corren, MD, Clinical Associate Professor of Medicine in Pediatrics in the Division of Clinical Immunology and Allergy at the University of California-Los Angeles, is to take the laboratory to the bedside. But do these enhancements in deposition of medication actually make a real difference in the clinic?

“We have seen a leveling off of the death rate from asthma at the same time we see yearly increases in incidence and prevalence,” he said. “For that
reason, I think we can look forward to increasing use of controller medication.”

ICS compounds are the current mainstay for treating bronchial asthma. Physicians still see large numbers of patients with age-related declines in lung function, recurrent exacerbations and persistent nocturnal symptoms, all impacting on their quality of life. Whether these are due to underdosing of medications, poor compliance or other reasons is still being debated.

There are a number of goals for the clinician to keep in mind. First, the patient wants to feel good, be free of wheezing, shortness of breath and to be able to sleep soundly. Second is to avoid attacks that interfere with a patient’s school or work. Third is to prevent the long-term sequelae of the disease attributed to airway remodeling.

“We know we can deal with the first two goals, but at the present time the third evades us,” he noted. “So, how do we prevent permanent changes in airway function?”

One method is to encourage adherence. Depending on the treatment, 30% to 40% of patients are not following prescribed therapies. These issues can be addressed by providing constant patient follow-up and giving the minimum possible dose while trying to limit side effects.

A benefit of HFA formulation over CFC is that they tend to have less oropharyngeal deposition. This leads to fewer cases of candidiasis (Richards J, et al. J Aerosol Med. 2001;14:197; Leach C, et al. Eur Respir J. 1998;12:1343).

“What is perhaps equally important is the distribution of the drug,” said Dr. Corren. “In the case of flunisolide HFA, 20% ends up in the central airways, 26% in the intermediate and 23% in the peripheral (< 2-microns) airways. This may be a very important distinguishing feature for both HFA flunisolide and HFA beclomethasone (BDP).”

With higher penetration levels into the lungs, it may be possible to lower dosages. In the case of flunisolide, the HFA formulation can be given at one-third of the dose of the CFC formulation and the HFA has the same efficacy at half the dose in CFC BDP.

However, clinicians often wonder if the lower dosing has an adverse impact on endpoints such as FEV1. Studies comparing HFA and CFC versions of
flunisolide or BDP, both show numeric superiority in FEV1 for the HFA formulations, although it did not reach statistical significance in the BDP study (Corren J, et al. Ann Allergy Asthma Immunol. 1998;12:1346).

“A far more important endpoint for judging asthma medications is asthma exacerbation rates,” said Dr. Corren.

Patients in a study by Bensch and Newman dropped out if they had an exacerbation. Patients prescribed HFA flunisolide had a 4% dropout rate at
12 weeks compared to 8% for the CFC and 22% for placebo (HFA vs. CFC p=.08). The study was not adequately powered to find significant differences, but was looking for equivalence. FEV₁ was similar with numeric superiority for the HFA preparation.

Measuring symptom-free days is another endpoint that should be assessed when evaluating asthma medications. Bensch and Newman compared the HFA and CFC formulations of flunisolide. When all symptoms were taken in total, there was a statistically significant difference favoring the newer formulation. Although the individual symptoms did not reach significance, there was still numeric superiority seen in many (Bensch G, Newman K. Poster presented at the Third Triennial World Asthma Meeting, 2001).

Quality-of-life issues can be used as another measuring stick. Juniper and colleagues studied BDP HFA and CFC formulations over a year. Despite the dosage for the CFC group being twice the HFA dose, there was a statistically significant difference in the overall quality of life favoring HFA (Juniper EF, Mol SJM. Eur Resp J.1999;14:523).

“You are giving less drug with about the same lung disposition, so why are there improvements in quality of life with the HFA medications?” asked Dr. Corren. “Perhaps it is due to the better distal penetration of the HFA variety.”

Historically, ICSs are considered to be safe drugs until reaching the very high doses used to treat severe asthma. There is still a reduced risk when compared to orally administered steroids.

One measure of the systemic impact of steroid administration is the provocative dose of a particular steroid that causes a 10% reduction in plasma cortisol. Unlike the CFC medications, 8 a.m. cortisol levels were normal 99.5% of the time for HFA flunisolide and BDP, regardless of doses administered. Every patient had normal morning cortisol after ACTH stimulation and there were no changes in 24-hour urinary cortisol. Integrated serum cortisols levels over 24 hours were unchanged compared to placebo (Martin R, et al. Am J Resp Crit Care Med. 2002;165:1377).

Davies and others looked at BDP HFA at a dose of 800 micrograms and compared it with CFC doses of 1,500. They found a much larger increase in
abnormal HPA function (15% CFC vs. 4% HFA). The two doses have similar levels of control, but there seemed to be a better safety margin with the HFA (Thompson PJ, et al. Respir Med. 1999; 93:366).

“One of the most outstanding concerns we all have is dosing children with inhaled steroids long term,” said Dr. Corren.

A study by Gillman looked at children aged 4 to 11 who were treated with flunisolide HFA at 340 micrograms a day, a negative control group of children taking cromolyn and a third grouptaking BDP CFC at 336 micrograms for 12 months. Those taking BDP CFC had a 5.1 cm increase in growth over a year compared to a 6.2 cm increase in both the flunisolide and cromolyn groups. There were no statistically significant differences since it was powered for equivalence (Gillman SA, et al. Clin Pediatr (Phila) .2002;41:333).

“If we were to summarize the safety of BDP and flunisolide HFA solutions, there is greater lung deposition that is not associated with increased systemic effects,” concluded Dr. Corren. “There appears to be no suppression of the HPA axis function at recommended doses and no suppression of pediatric growth with flunisolide. The same cannot be said about BDP HFA until we get more data.”

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