formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler

formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler

Accepted Manuscript Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-...

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Accepted Manuscript Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler Dominik Kappeler, Knut Sommerer, Claudius Kietzig, Bärbel Huber, Jo Woodward, Mark Lomax, Prashant Dalvi PII:

S0954-6111(18)30101-X

DOI:

10.1016/j.rmed.2018.03.029

Reference:

YRMED 5408

To appear in:

Respiratory Medicine

Received Date: 16 October 2017 Revised Date:

8 February 2018

Accepted Date: 28 March 2018

Please cite this article as: Kappeler D, Sommerer K, Kietzig C, Huber Bä, Woodward J, Lomax M, Dalvi P, Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler, Respiratory Medicine (2018), doi: 10.1016/ j.rmed.2018.03.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler Dominik Kappelera, Knut Sommerera, Claudius Kietziga, Bärbel Hubera, Jo Woodwardb, Mark Lomaxb, Prashant Dalvib* a

Inamed GmbH, Robert-Koch-Allee 29, Gauting, Germany

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Mundipharma Research Limited, Milton Road, Cambridge Science Park, Cambridge CB4 0GW, UK

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*Corresponding author

[email protected] [email protected]

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[email protected] [email protected]

[email protected]

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[email protected]

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[email protected]

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ACCEPTED MANUSCRIPT Abstract Introduction: A combination of fluticasone propionate/formoterol fumarate (FP/FORM) has been incorporated within a novel, breath-triggered device, named K-haler®. This low resistance device requires a gentle inspiratory effort to actuate it, triggering at an inspiratory flow rate of approximately 30 L/min; thus avoiding the need for coordination of inhalation with manual canister depression. The aim of the study was to evaluate total and regional pulmonary deposition of FP/FORM when administered via the K-haler device.

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Materials and Methods: Twelve healthy subjects, 12 asthmatics, and 12 COPD patients each received a single dose of 2 puffs 99mtechnetium-labelled FP/FORM 125/5 µg. A gamma camera was used to obtain anterior and posterior two-dimensional images of drug deposition. Prior transmission scans (using a 99mtechnetium flood source) allowed the definition of regions of interest and calculation of attenuation correction factors. Image analysis was performed per standardised methods.

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Results: Of 36 subjects, 35 provided evaluable post-dose scintigraphic data. Mean subject ages were 35.7 (healthy), 44.5 (asthma) and 61.7 years (COPD); mean FEV1 % predicted values were 109.8%, 77.4% and 43.2%, respectively. Mean pulmonary deposition was 26.6% (healthy), 44.7% (asthma), 39.0% (COPD) of the delivered dose. The respective mean penetration indices (peripheral:central ratio normalised to a transmission lung scan) were 0.44, 0.31 and 0.30. Conclusion: FP/FORM administration via the K-haler device resulted in high lung deposition in patients with obstructive lung disease but somewhat lesser deposition in healthy subjects. Regional deposition data demonstrated drug deposition in both the central and peripheral regions in all subject populations. EudraCT number: 2015-000744-42

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Keywords: Fluticasone propionate; formoterol fumarate; scintigraphy; deposition; radiolabelled

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ACCEPTED MANUSCRIPT 1

Introduction1

Flutiform® (FP/FORM) is an inhaler product containing a combination of fluticasone propionate (FP) and formoterol fumarate (FORM), approved for maintenance use in asthma following a comprehensive series of studies [1-10]. It is currently available within a conventional hydrofluoroalkane-propelled pressurised metered-dose inhaler (pMDI). Currently in development is the same FP/FORM formulation and canister incorporated within a novel, proprietary device, named K-haler® (Figure 1).

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Figure 1: The K-haler device

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Whilst the in vitro performances of the FP/FORM pMDI and K-haler device are thus essentially similar, the K-haler device is a breath-triggered inhaler (BTI) which automatically releases a dose of FP/FORM when a patient inhales. Therefore, the device avoids the need for the patient to coordinate manual canister depression with inhalation, which can be a problematic step in pMDI use for some patients [11-13]. The K-haler BTI has a low resistance, and is triggered by an inspiratory flow rate through the device of approximately 30 L/min. This combination of low resistance and a low trigger threshold ensures that only a gentle inspiratory effort is required to actuate the device. Thus virtually all patients can generate the requisite inspiratory effort, irrespective of the severity of their obstructive airways disease. Once the K-haler BTI is triggered, the quality of the aerosol plume released from the pressurised canister is independent of the patient. By contrast, for dry powder inhalers (DPIs), it is the patient’s inspiratory effort per se which deagglomerates the enclosed powder formulation and generates a respirable aerosol. This implies that aerosol quality may be impacted in some patients, particularly the elderly with severe COPD, young children or those with exacerbations, especially when using higher resistance DPIs [14-16].

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Glossary of less common abbreviations: FP/FORM = fluticasone propionate/formoterol; BTI = breathtriggered inhaler; DD = delivered dose; FPF = fine particle fraction; LPD = large particle dose; FPD = fine particle dose; SPD = submicron dose; IPR = inhalation profile recorder; ACF = attenuation correction factor; ROI = region of interest; PI = penetration index; ACI = Andersen Cascade Impactor; FRI = functional respiratory imaging; MMAD = mass median aerodynamic diameter

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ACCEPTED MANUSCRIPT Recent studies have evaluated the pulmonary and systemic bioavailabilities of fluticasone propionate and formoterol following administration of the FP/FORM K-haler BTI [17,18], as well as patient handling of this device [19]. The present study (EudraCT Number: 2015-000744-42; ffine [Fluticasone propionate/Formoterol: assessINg lung dEposition]) was undertaken to extend these investigations by evaluating pulmonary deposition with the K-haler BTI using two-dimensional gamma scintigraphy. 2

Materials and Methods

Radiolabelling procedure

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The study was performed at a single site in Germany (Inamed GmbH, Gauting, Germany) in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol and other relevant study documentation were approved by the local ethics committee and all subjects provided written informed consent.

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The manufacture of the radiolabelled product was approved by the local competent authority and was fully compliant with Good Manufacturing Practice regulations. 99mTechnetium was eluted as sodium pertechnetate (NaTcO4) in saline solution from a commercially available technetium generator (Mallinckrodt, Hennef, Germany). A two-fold amount of diethyl ketone was added to desalt the solution, i.e. extract 99mtechnetium from the saline solution. This resulted in two liquid phases which were separated. The technetium containing diethyl ketone layer was heated in a beaker to approximately 100°C until all the liquid evaporated. After allowing the beaker to cool to room temperature, 350 µL of ethanol was added to the beaker. Up to 45 µL of 99mtechnetiumethanol (dependent on specific radioactivity) was then pipetted in to an empty canister and the ethanol allowed to evaporate, followed by the canister being cooled to -196°C in liquid nitrogen. The target dose of radioactivity was 1.5 to 5 MBq at the time of product administration. A different canister containing FP/FORM, cooled by immersion in liquid nitrogen for 60 seconds, was then opened and its contents were transferred to the canister containing 99mtechnetium. The latter canister was then sealed by crimping on a new canister lid incorporating a metering valve and assembled into a K-haler device using a product-specific assembly rig. All canister components used were those employed during commercial manufacture of the K-haler device.

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The reproducibility of the radiolabelling procedure was assessed via testing of 3 radiolabelled batches (all derived from the same unlabelled product batch) in an Andersen Cascade Impactor (ACI; Copley Scientific, Nottingham, UK) operated at 60 L/minute (in accordance with release testing methods for the K-haler BTI). Five canisters from each of the 3 radiolabelled batches were assessed for delivered dose (DD) and 1 canister from each of the 3 batches was assessed for fine particle fraction (FPF). For the unlabelled product, three canisters were assessed for both DD and FPF. The DDs of the unlabelled and radiolabelled formulations, and the FPFs and stage-by-stage aerosol particle size distributions of the unlabelled formulation versus the radiolabelled formulation and radioactivity were compared. Two shots were fired into the ACI for DD estimation, and 10 for FPF. Drug masses were quantified via HPLC (Ultimate 3000, Dionex, Germering, Germany) whilst radioactivity was quantified using a scintillation counter (AM2005, MED, Dresden, Germany). In addition to the above, the DD and large particle dose (>5 µm; LPD), fine particle dose (<5 µm; FPD) and submicron dose (<1.1 µm; SPD) of the radiolabelled formulation were assessed for compliance with the FP/FORM K-haler BTI commercial product specifications. Furthermore, for reasons of safety and quality control, on dosing days the emitted dose of radioactivity from each subject’s inhaler was measured pre-dosing using a scintillation counter (target dose 1.5 – 5 MBq), and the DD, LPD, FPD

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ACCEPTED MANUSCRIPT and SPD of each inhaler were assessed post-dosing for conformance with the FP/FORM K-haler product specifications. 2.2

Subjects

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Forty-two male and female subjects (17 healthy volunteers, 13 asthmatics, 12 chronic obstructive pulmonary disease [COPD] patients) were screened to ensure that at least 30 (10 per group) completed the study. All subjects had to demonstrate satisfactory use of the K-haler BTI at screening. Key enrolment criteria were as follows: Healthy volunteers were aged 18 to 70 years, had normal lung function (forced expiratory volume in the 1st second [FEV1] >90% predicted) and were non-smokers for ≥12 months with a smoking history of <5 pack-years.

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Asthmatic subjects were aged 18 to 70 years, with persistent disease of ≥6 months’ duration and no change in asthma medication within the preceding 4 weeks, had FEV1 ≥60% to ≤90% predicted, were receiving GINA Step 2 (i.e. regular low dose inhaled corticosteroid [ICS]) treatment or above, and were non-smokers for ≥12 months with a smoking history of <5 pack-years.

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COPD patients were aged 40 to 70 years, had no change in COPD medication within the preceding 4 weeks, had FEV1 ≥30% to ≤50% predicted and an FEV1/FVC ratio of <70%, and a smoking history of ≥10 pack-years. Study design

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The study was of single-dose, open-label design. Subjects were trained to use the K-haler BTI using placebo K-haler devices fitted with an inhalation profile recorder (IPR) to monitor inspiratory flow rate and duration of inhalation. Training instructions included shaking the device for approximately 4 seconds, exhalation as long as comfortable, neutral head position, a slow and deep inhalation (preferably for 3-5 seconds) and a breath hold as long as comfortable. Following training, standing subjects self-administered a single dose of 2 puffs 99mtechnetium pertechnetate-labelled FP/FORM 125/5 µg (total dose 250/10 µg) via the K-haler device. FP/FORM K-haler devices without an IPR fitting were used to administer radiolabelled treatment. Post-inhalation and breath-hold, subjects exhaled into an exhalation filter prior to the acquisition of deposition images. Image acquisition and evaluation

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A gamma camera (LFOV Digitrac 66, MiE medical imaging electronics GmbH, Germany) with a 61 x 39 cm field of view, fitted with a low energy all-purpose parallel hole collimator, was used. The acquisition matrix was 256 x 256 pixels. Each subject underwent background radioactivity count and transmission scans (the latter using a 99mtechnetium flood source). The transmission scans allowed the calculation of tissue attenuation correction factors (ACFs), using the equation ACF = √(C0/C1) where C0 = counts without subject and C1 = counts with subject, as proposed by Newman et al [20]. The following regions of interest (ROIs) were defined: left and right lung, oropharynx/oesophagus/trachea and stomach. Anterior and posterior deposition images were then acquired post-inhalation commencing 2 minutes after inhalation of the radiolabelled formulation. Image analysis was performed in accordance with standardised 2D aerosol deposition imaging methods [20]. All acquired counts were corrected for background radiation, radioactive decay and tissue attenuation. 2.5

Outcomes

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ACCEPTED MANUSCRIPT The primary outcome was the whole lung deposition as a percentage of the DD. Secondary outcomes included the extrapulmonary (oropharyngeal, oesophageal, stomach and tracheal) deposition and the exhaled fraction (as percentages of the DD), and the penetration index (PI [peripheral/central deposition ratio normalized to a transmission lung scan]). 2.6

Statistics

Results

3.1

Radiolabelling validation

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Statistical analysis was restricted to descriptive statistics only, i.e. inferential analyses were not performed as no formal hypothesis was evaluated. A sample size of 10 completing subjects per group was thus not based on specific assumptions but was considered sufficient, based on previous studies [21-23], to allow the generation of meaningful summary statistics for deposition in each subject group. The primary analysis population for the scintigraphic analysis was the per protocol population, defined as all subjects with a transmission scan and a post-dose scintigraphic scan of sufficient quality to allow quantification of lung deposition, and no major protocol deviations. The safety population comprised all subjects who received radiolabelled treatment.

The DD ratio for the radiolabelled drug / unlabelled drug, and the FPF ratios for the radiolabelled drug / unlabelled drug and for radioactivity / unlabelled drug were all within 0.85 – 1.18 in accordance with the criteria defined by Devadason et al [24] (Table 1). Table 1: Delivered dose and fine particle fraction data for unlabelled FP/FORM, radiolabelled FP/FORM and radiolabel

FORM

4.15

FP

38%

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FPF (%*)

FP

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Delivered dose (µg)

Unlabelled drug (Reference) 103.6

FORM

39%

Radiolabelled drug (Test) 109.3 Ratio 1.06 4.37 Ratio 1.05 35% Ratio 0.92 33% Ratio 0.85

Radiolabel (Test) NA

38% 1.00 38% 0.97

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*Expressed as % delivered dose. Ratios expressed as Test:Reference FPF = fine particle fraction, defined as percentage of delivered dose with particles of size less than 5 µm; FP = fluticasone propionate; FORM = formoterol fumarate

In addition, the LPD, FPD and SPD of the radiolabelled formulation were all compliant with the FP/FORM K-haler product specifications. In view of the above, the radiolabelled formulation was considered both representative of the commercial product and satisfactory to quantify total lung deposition of FP/FORM with the K-haler device. Stage by stage aerosol particle size distribution data from an ACI operated at 60 L/min are presented in Figure 2.

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Whiskers represent 1 standard deviation.

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Figure 2: Aerosol particle size distribution data for unlabelled FP/FORM, labelled FP/FORM and radiolabel in an Andersen Cascade Impactor operated at 60 L/min

Unlike the comparisons for DD and FPF, individual stage comparisons indicated some differences between the unlabelled formulation versus the radiolabelled formulation and radioactivity in excess of the accepted 15% threshold [24], notably for stages 5, 6 and filter. Clinical

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3.2

A total of 36 subjects were dosed (12 in each group) and all completed the study (Figure 3).

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Figure 3: Patient Disposition

All subjects bar one subject with COPD had transmission scans and post-dose scintigraphic images which were of good quality and allowed estimation of FP/FORM deposition. Demographic and baseline characteristics of the 3 subject groups are summarised in Table 2.

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ACCEPTED MANUSCRIPT Table 2: Population demographic and baseline characteristics (per protocol population) Population Healthy

Asthma

COPD

(N=12)

(N=12)

(N=11)

35.7 (12.97)

44.5 (11.84)

61.7 (6.26)

12 / 0

9/3

7/4

Statistic

Age (years)

Mean (SD)

Male / female

n

FEV1 (Litres)

Mean (SD)

4.64 (0.29)

2.97 (0.56)

1.24 (0.37)

FVC (Litres)

Mean (SD)

5.85 (0.54)

4.71 (0.77)

2.96 (0.79)

% predicted FEV1

Mean (SD)

109.8 (8.57)

77.4 (7.53)

43.2 (6.82)

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Variable

N = Number of patients; n = number of applicable patients; SD = standard deviation; FEV1 = forced expiratory volume in the st 1 second; FVC = forced vital capacity

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Deposition data for the radiolabelled formulation is detailed in Table 3.

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ACCEPTED MANUSCRIPT Table 3: Deposition of radiolabelled FP/FORM aerosol expressed as % of delivered dose (per protocol population) Population Healthy

Asthma

COPD

(N=12)

(N=12)

(N=11) 39.0 (13.01)

Statistic

Lung (%)

Mean (SD)

26.6 (7.97)

44.7 (14.22)

90% CI

(22.4, 30.7)

(37.4, 52.1)

(31.8, 46.1)

25.9

50.7

45.2

15.1, 42.2

14.5, 62.4

16.3, 55.1

72.5 (7.75)

54.6 (13.46)

60.4 (12.81)

(47.6, 61.5)

(53.4, 67.4)

49.0

54.4

57.5, 84.4

37.4, 82.2

43.4, 82.9

0.9 (0.79)

0.7 (0.95)

0.7 (0.60)

(0.5, 1.3)

(0.2, 1.2)

(0.4, 1.1)

0.6

0.4

0.5

0.2, 2.6

0.2, 3.4

0.3, 2.2

Min, Max Extra Pulmonary* (%) Mean (SD) 90% CI

(68.5, 76.6)

Min, Max Exhaled air (%)

Mean (SD) 90% CI Median

Penetration index

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Min, Max

72.7

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Median

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Median

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Site

Mean (SD)

0.44 (0.11)

0.31 (0.11)

0.30 (0.14)

90% CI

(0.38, 0.50)

(0.25, 0.37)

(0.22, 0.37)

0.41

0.28

0.26

0.30, 0.66

0.14, 0.50

0.12, 0.63

Median

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*Comprises oropharyngeal, oesophageal, laryngeal and stomach ROIs

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FP/FORM = fluticasone propionate/formoterol fumarate SD = standard deviation; CI = confidence interval; Min = minimum; Max = maximum

Mean pulmonary deposition (expressed as a percentage of DD) was 27% in healthy volunteers, 45% in asthmatic subjects and 39% in COPD subjects. Mean pulmonary deposition (expressed as a percentage of metered dose) was 26% in healthy volunteers, 43% in asthmatic subjects and 38% in COPD subjects (further details in Table S1).

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ACCEPTED MANUSCRIPT In 7 of 12 asthma patients pulmonary deposition exceeded 50%, whilst deposition in excess of 40% was achieved by 6 of 11 COPD patients. The penetration indices in healthy volunteers, asthmatics and COPD patients were 0.44, 0.31 and 0.30, respectively. Deposition images from a single subject in each group, broadly exemplifying a typical deposition pattern for that cohort, are presented in Figure 4.

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Figure 4: Examples of posterior scintigraphic images from 3 subjects: A) Healthy (subject 07); B Asthma (subject 18); C) COPD (subject 41)

Discussion

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High and similar mean levels of FP/FORM pulmonary deposition were observed in asthma and COPD patients with overt degrees of airway obstruction in this study. Surprisingly somewhat lesser lung deposition was observed in healthy volunteers with normal lung function. Although all subjects in this study were naive to K-haler device use and received similar device training, it appears plausible that the healthy subjects’ naivety to all inhaler devices may have predisposed to errors, such as lingual or dental obstruction of airflow or not inhaling for sufficient duration, that were not detected during training or treatment administration.

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Lung deposition in patients with obstructive lung disease closely echoed earlier in vitro and functional respiratory imaging (FRI) findings for the same FP/FORM formulation within a pMDI. The FPF for FP/FORM pMDI, which has been approved in the EU since 2012, was consistently approximately 40% when tested at 28.3 and 60 L/min in an ACI [25] and was higher and more consistent across flow rates than for the 3 other ICS/LABA formulations evaluated (fluticasone propionate/salmeterol Accuhaler®, budesonide/formoterol Turbuhaler® and beclometasone/formoterol hydrofluoroalkane [HFA] pMDI). The potential for high lung deposition implied by these in vitro data was subsequently supported by FRI simulations employing threedimensional airway models of asthma patients’ lungs in conjunction with sharp or gradual inspiratory flow profiles. When the formulation characteristics of FP/FORM pMDI were applied to these asthmatic models, consistent pulmonary deposition estimates of 36 – 44% were obtained irrespective of flow rate (30 - 60 L/min) or inhalation profile [26]. The present in vivo study has thus replicated the FRI findings, with a notable consistency of results across the two investigative modalities. Furthermore, a pharmacokinetic study demonstrated that the relative lung bioavailability with FP/FORM K-haler was comparable to that of FP/FORM pMDI [17], however as the study was 10

ACCEPTED MANUSCRIPT aimed not to estimate the absolute lung bioavailability (by incorporating an additional arm using intravenous route of administration) the results do not allow any comparison with the lung deposition results from the present scintigraphy study.

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The high FP/FORM lung deposition demonstrated with K-haler BTI in this study compares favourably with other approved combination ICS/LABA formulations. In two scintigraphic evaluations, a pulmonary deposition fraction of 16% has been reported for fluticasone propionate/salmeterol HFA pMDI [21] whilst that for beclometasone/formoterol HFA pMDI was 31 to 34% [22]. Pharmacokinetic data for fluticasone furoate/vilanterol Ellipta® DPI indicate that the systemic bioavailabilities of its components following inhalation (which almost exclusively reflect pulmonary drug delivery and absorption) are 15% and 27%, respectively [27].

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The findings of the present study challenge the widely disseminated notion that small particles are the overwhelming determinant of pulmonary drug deposition [21,23,28]: the mass median aerodynamic diameter (MMAD) of FP/FORM being 3.2 – 3.5 µm [25]. The high lung deposition fraction seen with the FP/FORM K-haler product is likely attributable to the high FPF of this formulation [25] in conjunction with its favourable plume characteristics [29]. Interestingly, many of the publications which advocate the primacy of small particle size are based on extrafine beclometasone-HFA (Qvar®/Aerobec®; MMAD 1.2 µm [30]); but neglect to mention that formulation’s high FPF [31] or its advantageous plume character [32]. Similar considerations explain the high lung deposition that has been reported with the Respimat® soft mist inhaler (MMAD ~1 to 2 µm; [33,34]). Collectively, these observations support the authors’ view that FPF and plume character are major determinants of pulmonary drug deposition.

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Regional pulmonary deposition was also evaluated in our study. In keeping with other authors [35,36], we elected to report the penetration index although stage-by-stage ACI discrepancies between unlabelled drug versus radiolabelled drug / radioactivity exceeded those proposed to allow such inferences by an expert consensus group [24]. It is relevant, however, that the recommendations of Devadason and colleagues (stage-by-stage ratios within 0.85 – 1.18), whilst advancing harmonisation in this field, are in turn based upon European Medicines Agency guidelines [37]. The latter are not evidence-based and have not, to date, been shown to correlate with clinical outcomes. These limits may therefore be unduly stringent which is an important observation since the feasibility of satisfying these conditions when radiolabelling suspension and dry powder formulations (if not solutions) appears remote [21,23,35,38]. Thus, we consider our reporting of regional deposition to be appropriate: since the LPD, FPD and SPD of the radiolabelled product were all within release specifications for the commercial FP/FORM K-haler product, whilst the FPF data were also consistent with accepted criteria. The penetration indices in the present study imply that approximately 23-24% of the administered dose of FP/FORM reached the peripheral lung zone in COPD and asthma patients, with a corresponding figure of 30% in healthy volunteers. The slightly higher peripheral deposition estimate in healthy subjects is consistent with multiple previous scintigraphic studies [22,39,40,41] and is likely a consequence of the greater airway calibre in this population, allied to airways that are architecturally normal and free of pathology. Regional deposition data for FP/FORM pMDI are also available from FRI modelling, which employs three-dimensional models of the airways derived from computed tomography (CT) scanning. FRI has been shown to produce similar data to that obtained with combined three-dimensional single photon emission CT and CT (SPECT/CT) [42]. In their FRI study of 6 asthmatics (83% predicted mean FEV1), Holsbeke and co-workers estimated peripheral lung deposition (i.e. distal to the 9th airway 11

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generation) of FP/FORM (via pMDI) to be between 55% and 73% of the total lung dose [26]. Discrepancies in regional deposition estimates between Holsbeke at al’s FRI study and the present scintigraphic evaluation likely reflect methodological differences in the respective techniques employed. Inter alia, “peripheral” deposition in the present scintigraphic study encompasses the outer three quarters of the two-dimensional surface area (as advocated by Newman et al [20]); whereas in FRI it is conventionally defined as all deposition distal to the visible airway model (which extends to approximately the 9th airway generation). In addition, actual inhalations were required in the present scintigraphic study whereas the FRI study employed a variety of standardised inhalation profiles to perform deposition modelling. Nonetheless, despite their methodological differences and regional deposition estimates, both studies clearly imply the distal penetration of FP/FORM via the K-haler device which is supported by the available clinical data.

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In a study of 10 poorly controlled asthmatics treated with FP/FORM pMDI for 8 weeks, ventilation heterogeneity in the most distal (acinar) zone of lung was significantly improved from baseline and was normalised in half of the patients treated [43]. In addition to these physiological data, peripheral airway sequelae are evidenced by two large studies involving a total of 752 patients treated with FP/FORM for between 6 to 14 months [10]. A very low occurrence of severe exacerbations (approximately 2%) was seen in both these studies, considerably lower than in the great majority of comparable ICS/LABA trials [10, 44-46]. This is a noteworthy observation given that small airway dysfunction has been implicated in the expression of asthma exacerbations [47,48].

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The deposition data from this study also complement results from a recent K-haler device handling trial [19]. Of particular note in the latter, virtually all patients (304 of 307) were able to trigger the Khaler BTI to fire upon inspiration, including 86 COPD patients and 75 elderly patients (over 65 years of age). In the patients (<1%) who failed to trigger the device, this was unrelated to the severity of their airways disease. These data confirm that patients with lower inspiratory flow rates can readily trigger the K-haler BTI given its low trigger threshold and low inherent resistance – as confirmed by the lung deposition data in COPD patients in the present study with, on average, 43% predicted FEV1. In addition to the above, the handling study indicated that patients perceived the K-haler BTI very favourably in comparison to the two leading ICS/LABA DPIs: approximately 60 – 70% of patients preferred the FP/FORM K-haler BTI to the budesonide/formoterol Turbuhaler and fluticasone/salmeterol Accuhaler DPIs, a noteworthy observation given the importance of patient engagement with inhaler selection to subsequent adherence [49-52].

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A final observation concerns the utility of the K-haler device’s breath-triggered functionality in a reallife context. In the comparative handling and pharmacokinetic trials undertaken to date [17-19] successful device handling and pharmacokinetic bioavailability of the FP/FORM K-haler and FP/FORM pMDI in well trained healthy volunteers have been similar. However, in more general clinical settings approximately 15 – 30% of patients may experience difficulties coordinating inhalation and actuation with conventional pMDIs [11-13]. In such patients, another breath-actuated inhaler, the Autohaler® device, has previously been shown to facilitate high levels of pulmonary drug deposition (Newman 1991). Similar findings would be anticipated in the less coordinated population with the K-haler BTI, albeit this remains to be definitively established. Nonetheless, this putative benefit in conjunction with the lung deposition data from the present trial and recent device handling data suggest that the FP/FORM K-haler BTI may constitute a valuable addition to the therapeutic ICS/LABA armamentarium: to date no other ICS/LABA-containing BTIs are approved. 5

Conclusion

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ACCEPTED MANUSCRIPT In this scintigraphic study, pulmonary deposition of FP/FORM via the K-haler device was 27%, 45% and 39% of the delivered dose in healthy volunteers, asthmatic and COPD patients, respectively. The corresponding penetration indices in these populations were 0.44, 0.31 and 0.30, implying that approximately 23 - 30% of the total lung dose was deposited in peripheral zone. Acknowledgments

Trade mark statements  FLUTIFORM is a registered trade mark of Jagotec AG.

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K-HALER is a registered trade mark of Mundipharma AG.

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This study was sponsored by Mundipharma Research Limited. The authors would like to thank all study participants. Writing assistance to prepare this manuscript was provided by MD Medical Communications. Mundipharma Research Limited provided financial support for the preparation of the manuscript, including all article processing charges. All named authors meet the ICMJE criteria for authorship, have been involved in the analysis and interpretation of the data, the writing and review of the manuscript, in the decision to submit the manuscript for publication, and have given final approval of the version to be published.

ACCUHALER and ELLIPTA are registered trade marks of Glaxo Group Limited. TURBUHALER is a registered trade marks of AstraZeneca AB. AUTOHALER is a registered trade mark of 3M Company.

QVAR and AEROBEC are registered trade marks of Teva Pharmaceuticals International GmbH.

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RESPIMAT is a registered trade mark of Boehringer Ingelheim. Author Disclosure Statement

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Dr Dominik Kappeler was Principal Investigator at Inamed GmbH, the site at which the study was conducted. Mr Knut Sommerer, Mr Claudius Kietzig and Dr Bärbel Huber are employees at Inamed GmbH. Ms Jo Woodward, Mr Mark Lomax and Dr Prashant Dalvi are employees of Mundipharma Research Limited, the study sponsor. There are no other conflicts of interests related to this publication.

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Supplementary material

Table S1: Deposition of radiolabelled FP/FORM aerosol expressed as % of metered dose (per protocol population) Population Healthy

Asthma

COPD

(N=12)

(N=12)

(N=11)

Statistic

Lung (%)

Mean (SD)

25.6 (6.71)

43.3 (13.16)

37.6 (12.48)

90% CI

(22.1, 29.1)

(36.5, 50.1)

(30.8, 44.4)

25.8

47.0

43.5

13.9, 59.1

16.6, 54.2

53.5 (14.95)

58.9 (14.53)

(45.7, 61.2)

(50.9, 66.8)

Min, Max

16.0, 39.3

Extra Pulmonary* (%) Mean (SD)

71.0 (11.21)

Median Min, Max Exhaled air (%)

Mean (SD) 90% CI

74.9

46.2

54.7

53.5, 90.8

35.4, 78.5

42.7, 84.3

0.9 (0.82)

0.7 (0.92)

0.7 (0.61)

(0.5, 1.3)

(0.2, 1.2)

(0.4, 1.0)

0.6

0.3

0.4

0.2, 2.6

0.2, 3.2

0.2, 2.2

TE D

Median

(65.2, 76.8)

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90% CI

SC

Median

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Site

Min, Max

*Comprises oropharyngeal, oesophageal, laryngeal and stomach ROIs FP/FORM = fluticasone propionate/formoterol fumarate

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SD = standard deviation; CI = confidence interval; Min = minimum; Max = maximum

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Fluticasone/formoterol K-haler is a novel breath-triggered inhaler. Two-dimensional scintigraphy was used to quantify lung deposition. Study participants were healthy volunteers, asthma and COPD patients. Good lung deposition after single dose with fluticasone/formoterol K-haler.

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Mr Dominik Kappeler was Principal Investigator at Inamed GmbH, the site at which the study was conducted. Mr Knut Sommerer, Mr Claudius Kietzig and Dr Bärbel Huber are employees at Inamed GmbH. Ms Jo Woodward, Mr Mark Lomax and Dr Prashant Dalvi are employees of Mundipharma Research Limited, the study sponsor. There are no other conflicts of interests related to this publication.