Regional lung deposition and bronchodilator

AJRCCM Articles in Press. Published on September 28, 2005 as doi:10.1164/rccm.200410-1414OC

Regional lung deposition and bronchodilator response as a function of 2-agonist

particle size

Omar S Usmani1*, Martyn F Biddiscombe2, Peter J Barnes1 1

National Heart and Lung Institute, Imperial College London & 2Royal Brompton Hospital,

London SW3 6LY, U.K.

*Correspondence and requests for reprints should be addressed to Dr. Omar S Usmani Department of Thoracic Medicine, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K. E-mail:

o.usmani@ imperial.ac.uk

Facsimile:

+44 20 7351 5675

Phone number: +44 20 7351 8051

This research is supported by an academic grant from GlaxoSmithKline, Research & Development, U.K.

Running head:

2-agonist

regional lung deposition

Descriptor number: 172 Word count for the body of the manuscript: 3967

This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org.

Copyright (C) 2005 by the American Thoracic Society.

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ABSTRACT Rationale: Aerosol particle size influences the extent, distribution and site of inhaled drug deposition within the airways. Objectives: We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. Methods: In a randomized, double-blind, placebo-controlled study, 12 asthmatic subjects (FEV1 76.8±11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30µg-dose) of 1.5µm, 3µm, and 6µm mass median aerodynamic diameter, at slow (30-60 l/min) and fast (>60 l/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigrapy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15µg-dose) and 200µg MDI albuterol. Results: Smaller particles achieved greater total lung deposition: 1.5µm(56%), 3µm(50%), 6µm(46%), further distal airways penetration (0.79, 0.60, 0.36, respective penetration index), and more peripheral lung deposition (25%, 17%, 10%, respectively). However, larger particles (30µg-dose) were more efficacious and achieved greater bronchodilation than 200µg MDI albuterol; FEV1(ml); 6µm(551), 3µm(457), 1.5µm(347), MDI(494). Small particles were exhaled more 1.5µm(22%), 3µm(8%), 6µm(2%), whereas greater oropharyngeal deposition occurred with large particles (15%, 31%, 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles. Conclusions: Regional targeting of inhaled

2-agonist

to the proximal airways is more important than distal

alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.

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Abstract number of words: 249

Key Words: Aerosol, Particle Size, Radionuclide Imaging, Asthma, Beta-Adrenergic Agonists

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INTRODUCTION In many respects, the science of drug delivery to the lungs is still in its infancy. For too long, inefficient device systems have been accepted pragmatically for inhalation therapy in asthma. Provided enough drug reaches the lungs to achieve an adequate clinical response, these devices are considered satisfactory. However, there is a significant wasted portion of the dose that plays no part in the clinical improvement and may give rise to adverse effects. The challenge is to target inhaled medication to its clinically relevant effector cells within the lung, so as to optimize the therapeutic response and minimize potential adverse effects. Gamma scintigraphy is a powerful tool that has been widely used to visualize and characterize intrapulmonary drug delivery in asthmatic subjects (1). Numerous studies have quantified lung deposition patterns, but often in isolation to clinical outcomes (2). The few studies that incorporated efficacy variables, either using indirect radiolabeling techniques involving inert non-pharmacological monodisperse particles (3-7), or by using direct physically radiolabeled

2-agonist

aerosols (8-17), have collectively been inconclusive with regards to the

relationship of regional airways bronchodilator deposition with therapeutic response. Commercial polydisperse inhaler devices, which lack the specificity of airways targeting, were primarily employed within these studies to investigate the advantages of new aerosol delivery systems, rather than explore the science of inhaled drug delivery. Monodisperse pharmacological aerosols, however, make it possible to undertake translational aerosol research, accurately exploring in vitro concepts of aerosol particle behavior within the human airways in vivo (18). They are composed of uniform sized particles where the majority of the aerosol drug mass is within a narrow size distribution and therefore, have greater discriminative power than polydisperse aerosols to explore differences due to drug particle size. It is well recognized that of the aerosol characteristics, drug particle size is the major

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determinant governing the site of airway deposition of inhaled medication (19). We previously described our use of a spinning-disk aerosol generator to produce monodisperse albuterol aerosols and reported 6µm and 3µm particles were more potent bronchodilators that 1.5µm particles in mild-moderate asthmatic subjects (20). We proposed larger particles were better matched to their target site of action. Our hypothesis is that the regional airways distribution of

2-agonist

is important in

modulating the bronchodilator response and, by altering intrapulmonary deposition through aerosol particle size, we may be able to optimize inhaled drug delivery. The aim of this study, therefore, was to investigate the dynamic relationship between albuterol particle size, regional lung deposition, inspiratory flow, and bronchodilator response, in order to build up a profile of the optimal aerosol delivery characteristics. We used 2D planar imaging to assess the lung and extrathoracic deposition patterns of three sizes of technetium-99m-labeled monodisperse albuterol aerosols in mild-moderate asthmatic subjects, with simultaneous measures of efficacy and tolerability. Some of the results of this study have been previously reported in the form of an abstract (21,22).

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METHODS Additional details on the research methods are available in the online supplement.

Subjects Twelve stable mild-moderate asthmatic subjects (FEV1 76.8±11.4% predicted) gave their written informed consent to participate in this study approved by the local ethics committee (Table 1). Each showed

15% bronchodilator improvement in FEV1 after inhaling 200µg

albuterol from a metered-dose inhaler (MDI) and spacer. Subjects were controlled on 500µg inhaled beclomethasone dipropionate daily, but none were receiving long-acting

2-agonist

or

oral anti-asthmatic medication. Seven subjects were steroid-naïve.

Aerosol Generation, Radiolabeling and Imaging The generation and radiolabeling of monodisperse (geometric standard deviation, GSD 60 l/min (fast inhalation). Following aerosol delivery and imaging, spirometry, cardiovascular measurements and samples for plasma potassium were taken at 10minutes from the beginning of inhalation and at 10-minute intervals for 60 minutes, then every 15-minutes to 90 minutes. For efficacy measurements, the best value (maximal) out of two was taken at each time-point, whereas only single measurements were undertaken for tolerability markers.

Statistical Analysis For the efficacy and tolerability variables, the change in each measurement from baseline (pretreatment) values were plotted at each timepoint for the duration of the study (time 0-90 minutes) to derive a time-response curve for each subject. The area under the time-response curve (AUC) was calculated using trapezoidal integration, and this value was weighted (wAUC) for duration of time (28). For each biological variable, the mean of all the wAUCs from the 12 subjects was calculated and this value was used in the statistical analysis.

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Comparison between the clinical effects of each treatment, and between the radiolabelled deposition data of each treatment, were undertaken using parametric analysis of covariance (ANCOVA) including factors for subject, period, treatment and multiple comparisons. Based on our previous data (20), with 12 subjects there was 80% power to detect a clinically relevant difference of 0.25 liters in FEV1 between the treatments, assuming a significance level of 0.05 and an estimate of variability of 0.25 liters.

RESULTS Radioaerosol Deposition Images Typical deposition patterns for the three monodisperse aerosols are shown (Figures 1 and 2). Although the asthmatic subjects were stable and asymptomatic, regional ventilatory inhomogeneity was evident, as patchy aerosol deposition within the lung images, which suggested native airway obstruction.

Total Lung and Extrathoracic Deposition Total lung deposition (TLD) was greater with the 1.5µm aerosols compared to the 6µm (p < 0.05) and 3µm aerosols (p = 0.40) (Table 2). Oropharyngeal deposition increased with increasing particle size, whereas the exhaled aerosol fraction was greatest with the 1.5µm aerosols. No significant difference in mediastinal deposition and mouthpiece retention was noted between the three particle sizes.

Lung Distribution and Regional Deposition Penetration index values increased with decreasing particle size implying 1.5µm particles penetrated further into the lung periphery, whereas 6µm particles were more proximally

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distributed within the airways (Table 2). Differences were highly significant between all particle size comparisons (p < 0.001). Regional deposition analysis expressed as a percentage of TLD confirmed peripheral region deposition was significantly greater with smaller particles in the order 1.5µm > 3µm > 6µm (p < 0.001) (Table 2). Conversely, 6µm particles achieved significantly more combined central and intermediate (C+I) region deposition compared with the other particles (p < 0.001). Similarly, when expressed as a percentage of the delivered dose, peripheral region deposition increased significantly with decreasing particle size (all comparisons p < 0.001). However, although C+I as a percentage of delivered dose was greatest for the 6µm particles, differences between particle sizes were not significant.

Clinical Assessment Pre-treatment baseline FEV1 values were similar between the eight study groups and the screening value (see online supplement Table E5, p > 0.05). Larger particles produced greater FEV1 (ml, means ± SD) bronchodilation in the order 6µm > 3µm > 1.5µm, at both 15µg (484±183, 420±121, 337±169, respectively) and 30µg doses (551±221, 457±200, 347±172, respectively). Likewise, particle size effects with FEF25-75 and PEF mirrored those of FEV1 in that greater airway responses were achieved with increasing particle size (see online supplement Table E6). These measurements showed significant difference between 6µm and 1.5µm aerosols at both doses, but not between other particle size comparisons. Particle size differences in FVC were not significant. All treatments (monodisperse and MDI) demonstrated highly significant increases in all lung function measurements compared to placebo (p < 0.001). The 6µm monodisperse aerosol at the 30µg dose was a more potent bronchodilator than 200µg MDI albuterol (FEV1, 494±193), and achieved a comparable FEV1 response to the MDI dose at a 15µg dose. The study was not powered to test equivalence with the MDI.

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Bronchodilation, judged by FEV1, was greatest at the 30µg dose compared to the 15µg dose for each particle size, but no significant difference was noted between doses. In addition, no significant difference was observed in the tolerability measurements for each particle size / dose combination compared to placebo, or between doses for the same particle size comparison (see online supplement Table E6). Time-response profile curves for FEV1 showed there was a distinct and sustained separation of bronchodilator particle size effects throughout the duration of the study, whereby the 1.5µm particles were unable to achieve the response obtained with the 6µm and 3µm particles (Figure 3).

Inspiratory Flow Effects on Deposition and Clinical Response Mean (± SD) inspiratory flows for slow and fast inhalation were 30.8±4.7 l/min and 67.1±16.7 l/min, respectively. Fast inhalation increased TLD for 1.5µm particles ( 4.6%, p < 0.05), but decreased for 3µm ( -1.4%, p = 0.42) and 6µm ( -24.7%, p < 0.001) particles (Figure 4). Oropharyngeal deposition increased for all particle sizes, but this was significantly greater for the larger particles (p < 0.001). Particle distribution was shifted more centrally (Figures 5 and 6A), and these differences were highly significant compared to slow inhalation (p < 0.001). There was no significant difference in FEV1 for 1.5µm aerosols, but a significant decrease was observed for 3µm and 6µm aerosols (p < 0.001) (Figure 6B). No correlation was observed of either total lung dose, or regional deposition, with particle size and lung function measures at either slow or fast inhalation flows (see online supplement Tables E7 and E8, respectively).

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DISCUSSION This is the first study to combine the assessment of regional airways drug deposition using radiolabeled monodisperse albuterol aerosols, with the simultaneous measure of clinical response, in order to investigate the science of bronchodilator particle size effects in vivo. We have shown that by using different aerosol particle sizes to deliver inhaled

2-agonist

to lung

regions containing the target effector cells and, by reducing aerosol losses in regions where albuterol has little effect, we may optimise inhaled bronchodilator delivery to the lungs. Our data shows new evidence that clearly demonstrates the importance of the regional lung deposition of albuterol in determining the bronchodilator response in asthma and, both drug particle size and inspiratory flow are important factors in achieving this aim. Although

2-receptor

density is greatest in the alveolar region (29), airway smooth

muscle is relatively sparse, being predominantly located in the conducting airway region which is where

2-agonist

should be deposited to achieve effective bronchodilation (30). Despite

greater total lung deposition and further distal airways penetration with smaller 1.5µm albuterol particles during slow inhalation, we found larger particles achieved significantly greater bronchodilation. We reasoned the different innate physical deposition characteristics of the particle sizes allowed selective regional airway targeting, in that, albuterol was favorably directed to the conducting airways smooth muscle using larger particles, while smaller particles were preferentially directed to peripheral alveoli (31,32). Additionally, the marked increase in airways surface area towards the lung periphery will have diluted the topical mucosal drug concentration within the alveoli compared to the proximal conducting region (33). The successful delivery of inhaled medication to the lungs also requires minimal upper airway aerosol losses. Smaller particles largely bypass the filtering mechanisms and abrupt airway geometry of the upper airways, which will have accounted for their less oropharyngeal deposition, whereas larger particles which deposit chiefly by impaction due to their greater

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inertia are more likely to leave the inspired airstream during sudden changes in airflow direction, particularly in the oropharynx and at airway bifurcations. It is not entirely surprising that despite delivering the largest lung dose, the smaller particles were also exhaled the most, as our previous in vitro data have shown 1.5µm particles can remain airborne for a considerable time, even with the breath-hold pause maximizing the effect of gravitational sedimentation (23). Particles that remain airborne in the larger airways are likely to be exhaled due to a greater settling distance before coming into contact with the airway walls. Hence, it would be expected much less drug deposited in the conducting airway region for smaller particles. Upon reaching the lungs, by virtue of their particle size deposition characteristics, central and intermediate (C+I) region aerosol deposition, as a proportion of the lung dose, was significantly greater with 6µm particles, whereas 1.5µm particles favoured peripheral region deposition (Table 2). The C+I region of interest encompasses the majority of the conducting airways (generations 0-16), where

2-agonists

should be directed (34). Yet, C+I deposition

quantified as a percentage of the delivered dose revealed similar values between the three particles. So how can this lead to a significant difference in clinical efficacy? Herein lies a limitation of 2D planar imaging of the 3D lung structure, as overlying alveolar deposition may have obscured the true conducting airways dose in the C+I region. However, this study is unique as our planar images are distinct representations of monodisperse aerosol distributions within the airways, whose specificity allows us to delineate the very nature of the airways contributing to the C+I region. Taken together with experimental data that predicts 1.5µm particles deposit mainly in the alveolar region (31), we infer the C+I region of interest for the 1.5µm particles is mainly drug in overlying peripheral alveoli rather than in conducting airways, whereas for the 6µm particles our imaging data supports the C+I region as deposition predominantly in the conducting airways. Although imaging residual radioactivity in the lungs at 24-hours may have given another estimate of alveolar deposition (35), this was not a feasible

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option in our study due to the relatively quick dissociation of radiolabel from drug (see online supplement Figure E1). Physiological pulmonary function assessment including spirometry is unable to accurately differentiate between the distinct conducting and alveolar airway regions or small (