ORIGINAL RESEARCH

Aerosol Deposition of Inhaled Corticosteroids/Long-Acting b2-Agonists in the Peripheral Airwaysof Patients with Asthma Using Functional RespiratoryImaging, a Novel Imaging Technology

Takashi Iwanaga . Takenori Kozuka . Junko Nakanishi .

Koji Yamada . Osamu Nishiyama . Hiroyuki Sano .

Takamichi Murakami . Yuji Tohda

Received: February 7, 2017 / Published online: April 3, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Drug deposition in the periph-eral airways has been reported to differ betweenpressurized metered dose inhalers (pMDIs) anddry powder inhalers (DPIs). This study wasconducted to determine the drug depositionfraction from three inhaled corticos-teroids/long-acting b2-agonists (ICS/LABA)combination products for inhalation in theperipheral airways.Methods: An airway deposition model wasconstructed using computed tomography (CT)images obtained in patients with asthma.

Functional respiratory imaging was used todetermine the airway deposition of Flutiform�

(Kyorin Pharmaceutical), Symbicort� (As-traZeneca and Astellas Pharma), and Relvar�

(GlaxoSmithKline K.K.) without actual druginhalation based on airway images from CT andcomputational fluid dynamics using drug par-ticle size.Results: The mean drug deposition fractionsand standard deviations (SDs) in the peripheralairways for Flutiform, Symbicort, and Relvarwere 30.33% ± 1.89%, 18.95% ± 2.03%, and6.58% ± 0.98% for ICS, and 29.17% ± 1.81%,17.24% ± 1.87%, and 11.30% ± 1.42% forLABA, respectively, showing that significantlyhigher proportions of ICS and LABA weredeposited to the peripheral airways from Fluti-form than from Symbicort and Relvar(p\0.001). The mean drug deposition fractionsand SDs in the entire lung for Flutiform, Sym-bicort, and Relvar were 46.18% ± 1.29%,28.85% ± 0.78%, and 13.01% ± 0.66% for ICS,and 44.34% ± 1.23%, 26.32% ± 0.71%, and20.02% ± 0.80% for LABA, respectively, show-ing that significantly higher proportions of ICSand LABA were deposited to the lung fromFlutiform than from Symbicort and Relvar(p\0.001).Conclusions: Flutiform (pMDI) was shown toprovide significantly higher drug depositionfraction to the central/peripheral airways thanSymbicort (DPI) and Relvar (DPI). It is suggestedthat Flutiform may provide a potent therapeutic

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Electronic supplementary material The onlineversion of this article (doi:10.1007/s41030-017-0036-4)contains supplementary material, which is available toauthorized users.

T. Iwanaga � O. Nishiyama � H. Sano � Y. Tohda (&)Department of Respiratory Medicine andAllergology, Kindai University Faculty of Medicine,Osakasayama, Osaka, Japane-mail: tohda@med.kindai.ac.jp

T. Kozuka � T. MurakamiDepartment of Radiology, Kindai University Facultyof Medicine, Osakasayama, Osaka, Japan

J. Nakanishi � K. YamadaDepartment of Central Radiology, Kindai UniversityHospital, Osakasayama, Osaka, Japan

Pulm Ther (2017) 3:219–231

DOI 10.1007/s41030-017-0036-4

option for various asthma patients, includingthose who have difficulty using DPIs.Trial registration: UMIN000022840.Funding: Kyorin Pharmaceutical Co., Ltd.

Keywords: Asthma; Drug deposition;Flutiform; Functional respiratory imaging;Inhaled corticosteroids/long-acting b2-agonists(ICS/LABA); Inhaled particle; Peripheral airways

INTRODUCTION

Asthma is recognized as a chronic inflammatorydisease of the airways, and is accompanied byairway remodeling resulting from persistentinflammation. While recent progress in tech-niques for objective assessment of airwayobstruction and inflammation contribute to theunderstanding of pathology in each airwayregion, it has been shown that the peripheralairways in patients with asthma has unevendistribution of airway wall thickening caused byinflammation and luminal narrowing/obstruc-tion caused by sputum, with more severeinflammation in the peripheral airways than inthe central airway. In addition, profound cor-relation between peripheral airways lesions andnocturnal wheezing has been reported, reveal-ing that inflammation is widely found in notonly the central airway, but also the peripheralairways into alveoli in asthma patients [1].

From these pathological perspectives,inflammation control not only in the centralairway, but also in the peripheral airways isimportant to achieve complete asthma controlas defined by the Asthma Prevention andManagement Guidelines (JGL2015) [2].

Inhaled corticosteroids (ICSs) are establishedas first-line therapy for long-term managementof asthma, and the concomitant use oflong-acting b2-agonists (LABAs) is recom-mended for asthma not well controlled by ICSsalone. In Japan, four different combinations ofan ICS and a LABA are currently available andsupplied in two dosage forms: a pressurizedmetered-dose inhaler (pMDI) and a dry powderinhaler (DPI). It has been shown that drugdeposition in the peripheral airways differsbetween pMDIs and DPIs due to differences in

particle size and flow rate, etc. [3], and is pre-sumed difference of treatment effect.

The distribution research in airways andlungs of patients with pulmonary diseases wasconducted by using single photon emission CT(SPECT) or computed tomography (CT). How-ever, those methods used radiolabeled aerosols,and problems of radio-labeled exposure wasbothered.

Meanwhile, functional respiratory imaging(FRI) is one of the computational fluid dynam-ics (CFD) technology, which is an imagingtechnology for analysis of drug depositionwithout actual drug inhalation based on airwayimages from CT and FRI using the factor such asdrug particle size and flow rate, has recentlybeen validated [4] and is being introduced forclinical use to determine the airway depositionof inhaled drugs [5].

The objective of this study was to evaluate byFRI the difference of drug deposition betweenpMDI and DPIs using FRI in Japanese patientswith asthma. Drug deposition fraction wasimaged and calculated from three ICS/LABAcombination products for inhalation, which arewidely used in Japan, in the peripheral airways:Symbicort�, a combination of budesonide/for-moterol fumarate hydrate (BUD/FM) via DPI,AstraZeneca and Astellas Pharma; Relvar�, acombination of fluticasone furoate/vilanteroltrifenatate (FF/VI) via DPI, GlaxoSmithKlineK.K.; and Flutiform�, a combination of flutica-sone propionate/formoterol fumarate hydrate(FP/FM) via pMDI, Kyorin Pharmaceutical.

METHODS

Subjects

Patients who met all of the following inclusioncriteria were eligible for the study: an outpatientaged 20 years or older with a diagnosis ofasthma; mild to moderate persistent asthma asdefined by the Asthma Prevention and Man-agement Guidelines 2015; good or betterasthma control [Asthma Control Test (ACT)C20]; and able to communicate. Patients withevidence of chronic obstructive pulmonarydisease (COPD) or respiratory infection and

220 Pulm Ther (2017) 3:219–231

those who were, in the opinion of the investi-gator, inappropriate for the study were excludedfrom the study.

Data Collection

At enrollment (Visit 0), the following patientinformation was collected: gender, birth date,disease type and severity, duration of disease,treatment step, anti-asthmatic drugs used atenrollment, concurrent diseases, smoking, andasthma control level measured by ACT (25points: complete control, 20–24 points: wellcontrol,\20 points: poor control). In addition,respiratory function testing was performed afterinhalation of a bronchodilator only in theabsence of asthma exacerbation (at least weeklyoccurrence of asthma symptoms or use ofshort-acting b2-agonists): spirometry [forcedexpiratory volume in 1 s (FEV)1, FEV1% pre-dicted, FEV1/forced vital capacity (FVC), FVC,_V50, _V25, % _V50, and % _V25] and impulseoscillometry system (IOS) for measurement ofairway resistance and reactance (R5, R20,R5–R20, X5, AX, Fres, R5 ex-in, R20 ex-in,R5–R20 ex-in, X5 ex-in, AX ex-in, and Fresex-in).

Subjects with asthma exacerbation at Visit 1were discontinued from the study withoutundergoing a CT scan. For subjects with noevidence of asthma exacerbation, chest CTimages (tube voltage 120 kV, tube current100–750 mA, slice thickness 0.625 mm, andpitch 1.375:1) associated with TLC and FRCwere taken via USB spirometer (Spirostik; Ger-atherm Respiratory GmbH, Kissingen, Ger-many). CT scan data, flow pattern data collectedvia Spirostik, and CT scan form were anon-ymized and stored on a DVD before being sentto Fluidda NV (Kontich, Belgium) for dataanalysis via the clinical research supportorganization.

Spirostik, a USB spirometer not approved inJapan, but approved and used in 28 countries,was used, because (1) FRI analysis requires CTimages associated with total lung capacity (TLC)and functional residual capacity (FRC), and thusCT scanning with flow patterns being moni-tored, and (2) a mouthpiece must be non-metal,

while those for spirometers approved in Japancontain metals. The airway model at TLC wasused for CFD flow stimulation by smoothingthe airway wall. The TLC was after deep inspi-ration, and FRC was after expiration in lungsand lobes.

FRI Analysis

This study was conducted by Fluidda NV (Kon-tich, Belgium), investigated the lung depositionof inhaled particles emitted by Flutiform pMDIusing FRI versus Symbicort and Relvar DPIs. Inthe FRI workflow, patient-specific anatomicalimages of CT scans are combined with func-tional information that is calculated usingcomputational fluid dynamics. Patient-specificthree-dimensional models of the airway andlungs were extracted from medical images andsuitable boundary conditions were definedbased on patient-specific internal airflow distri-bution. For both the inspiratory and expiratoryscans, the patient-specific lung lobes have beenreconstructed. All CT data were entered intosoftware package (Mimics 15.0; Materialise,Leuven, Belgium), and lobar and airway seg-mentation were analyzed.

Based on the values of mass median aerody-namic diameter (MMAD) and geometric stan-dard deviation (GSD) showed in Table S1,lognormal particle distributions were created.From this distribution, the cumulative mass ofall the particles smaller than 5 lm in diameterwas calculated, which was considered as thetheoretical fine particle fraction (FPF), withoutany losses taken into account. In the next step,this distribution was scaled such that the theo-retical FPF equals the measured FPF, due topossible losses in the inhaler and pre-separator.From MMAD and GSD, the lognormal particlesize distribution was calculated and thegeometries were reverse-engineered into 3DCAD models. For each of the patients, thepatient-specific lower airway was coupled to anaverage upper airway from Fluidda’s databaseand the inhaler. On these models, the CFDsimulations were performed. CFD simulations(Fluent, Ansys 14.0) were performed on thecoupled 3D models using the following

Pulm Ther (2017) 3:219–231 221

strategy: fully tetrahedral mesh (generated inTGrid, Ansys 14.0) with around four millioncells; percentage of flow exiting the modeltowards a lobe equals the relative lobar expan-sion as obtained from the patient specific in-and expiratory lobar 3D models; selectedinhalation profiles were applied at the inhalerinlet to take the turbulence that was generatedby the device. Each device was tested under itsmost optimal conditions; at respective usualdosages and an inspiratory flow rate of 60 L/minfor Symbicort (BUD 200 lg, FM 6 lg) and Relvar(FF 100 lg, VI 25 lg), and 30 L/min for Fluti-form (FP 125 lg, FM 5 lg). Data of particle sizedistribution of each drug were obtained usingAndersen Cascade Impactor (ACI) for Flutiformand Symbicort and Next Generation Impactor(NGI) for Relvar, since there were no dataavailable for Relvar using ACI. The detailedmethod for FRI was previously reported [4]. Thelobe definition was the same as that used withthe CT image (right upper and right middlelobes, right lower lobe, left upper lobe, leftlower lobe).

Patient-related variables concerning airwayvolume [total airway volume, peripheral air-ways volume and lung lobar airway volume(iVaw)] and airway resistance [total airwayresistance, peripheral airways resistance, andlung lobar airway resistance (iRaw)], as well asdrug-related FRI variables concerning deposi-tion fraction (expressed as the percentage of thedose administered) and absolute deposition ofeach active ingredient from individual productsin the lung, peripheral airways, and each lobe ofthe lung were determined.

Endpoints

The primary endpoint was the FRI-based drugdeposition fraction in the peripheral airways.The secondary endpoint was the FRI-based drugdeposition fraction in the lung and each lobe ofthe lung.

Target Sample Size and its Rationale

In a previous overseas study, the lung deposi-tion of inhaled particles emitted by three

metered-dose inhalers was compared in foursubjects. Given the previously reported samplesize, the target sample size of six subjects asthose who successfully completed the study wasselected for the present study to assess theperipheral airways deposition in asthmapatients in an exploratory manner.

Statistical Analyses

Analysis of variance (ANOVA) was performedfor calculated drug deposition from each pro-duct in the entire lung and peripheral airwaysto prepare boxplots with the median,interquartile range, maximum, and minimum.A whisker from the maximum to the minimumwas less than 1.5 times the interquartile range,and outliers were individually plotted. Themean values and the standard deviations (SDs)were given for every drug. ANOVA tables weregenerated, in which the p values were gener-ated based on Satterthwaite’s approximationfor degrees of freedom. A multiple comparisonz-test with confidence intervals was performedto test the differences in deposition betweenFlutiform and the other products. p valuessmaller than 0.05 were considered statisticallysignificant.

Compliance with Ethics Guidelines

This study was conducted in compliance withthe ethical and scientific principles based on theDeclaration of Helsinki (revised in Fortaleza in2013), the Ethical Guidelines for Medical andHealth Research Involving Human Subjects(enforced on December 22, 2014), the MedicalExposure Guidelines 2006, and related laws andregulations, as well as in accordance with theprotocol approved by the Ethics Committee ofKindai University Faculty of Medicine. For themanagement of conflict of interest, the studywas also conducted in line with the Guidancefor Management of Conflict of Interest (Healthand Labour Sciences Research), the Trans-parency Guideline for the Relation betweenCorporate Activities and Medical Institutions(Japan Pharmaceutical Manufacturers Associa-tion), and the Problems Relating to

222 Pulm Ther (2017) 3:219–231

Investigator-initiated Clinical Trials in Japanand Countermeasures (proposed by the ScienceCouncil of Japan) in such a manner that thestudy results would not be influenced by theinterest of the research funder. While no Japa-nese laws or regulations, including the MedicalService Act, restrict the medical exposure dose,the radiation exposure dose in this study waslower than the exposure limit [volume CT doseindex (CTDIvol) of 25 mGy] specified in theAmerican College of Radiology Guidelines [6],indicating that participation in the study wouldinvolve no health hazards.

Prior to enrollment of patients into thestudy, written voluntary consent was obtainedfrom each subject who received a detailedexplanation of the study from the investigatorbased on an informed consent form approvedby the ethics committee. In addition, a subjectidentification code was obtained by enteringeach subject’s name in a correspondencetable to assure anonymity of subjects.

RESULTS

Patient Characteristics

The characteristics of all six patients are shownin Table 1. The study population consisted ofthree males and three females. The disease typewas atopic in three subjects and non-atopic inthree subjects, the disease severity was mildpersistent in four subjects and moderate persis-tent in two subjects, and the treatment was Step2 in four subjects and Step 3 in two subjects.Two subjects had concurrent disease (allergicrhinitis in one subject and other disease in onesubject), and five subjects had a smokinghistory.

Drug Deposition Fraction in the PeripheralAirways

The mean drug deposition fractions (and SDs)in the peripheral airways for Flutiform, Symbi-cort, and Relvar were 30.33% ± 1.89%,18.95% ± 2.03%, and 6.58% ± 0.98% for ICS,respectively (Fig. 1a), and 29.17% ± 1.81%,

Table 1 Patient characteristics

No. of patients 6

Gender

Male 3 (50.0%)

Female 3 (50.0%)

Age (years)a 62.2 ± 7.7

Disease duration (years)a 11.5 ± 17.6

Disease type

Atopic 3 (50.0%)

Non-atopic 3 (50.0%)

Severity

Mild persistent 4 (66.7%)

Moderate persistent 2 (33.3%)

Treatment step

Step 2 4 (66.7%)

Step 3 2 (33.3%)

Complications (Allergic disease)

No 4 (66.7%)

Yes 2 (33.3%)

Allergic rhinitis 1

Other 1

Smoking history

No 1 (16.7%)

Ex-smoker 5 (83.3%)

Lung functiona

Spirometry

FEV1 (L) 2.43 ± 0.21

FEV1% predicted (%) 95.32 ± 19.83

FEV1/FVC (%) 79.87 ± 4.57

FVC (L) 3.06 ± 0.34

_V 50 (L/s) 3.01 ± 0.70

_V25 (L/s) 0.84 ± 0.23

% _V50 (%) 87.67 ± 24.05

% _V25 (%) 66.85 ± 23.11

IOS

R5 (kPa/(L/s)) 0.21 ± 0.04

R20 (kPa/(L/s)) 0.18 ± 0.04

R5–R20 (kPa/(L/s)) 0.03 ± 0.02

X5 (kPa/(L/s)) -0.08 ± 0.03

Ax (kPa/L) 0.37 ± 0.21

Fres (1/s) 16.68 ± 6.51

R5 ex-in (kPa/(L/s)) 0.05 ± 0.02

Pulm Ther (2017) 3:219–231 223

17.24% ± 1.87%, and 11.30% ± 1.42% forLABA, respectively (Fig. 1b), showing that sig-nificantly higher proportions of ICS and LABAwere deposited to the peripheral airways fromFlutiform than from Symbicort and Relvar(p\0.001).

Drug Deposition Fraction in the EntireLung

The mean drug deposition fractions (and SDs) inthe entire lung for Flutiform, Symbicort, andRelvar were 46.18%± 1.29%, 28.85% ± 0.78%,and 13.01% ± 0.66% for ICS, respectively(Fig. 2a), and 44.34%± 1.23%, 26.32% ± 0.71%,and 20.02%± 0.80% for LABA, respectively

(Fig. 2b), showing that significantly higher pro-portions of ICS and LABA were deposited to thelung from Flutiform than from Symbicort andRelvar (p\0.001).

Drug Deposition Fraction in Each Lobeof the Lung

For both ICS and LABA from all of the threeproducts, the drug deposition fractions in eachlobe of the lung were higher in the lower lobe inthe right lung and the upper/lower lobe in theleft lung than in the upper/middle lobe in theright lung. The mean drug deposition fractions(and SDs) in each lobe of the lung for Flutiform,Symbicort, and Relvar were 8.78% ± 4.98%,5.45% ± 2.89%, and 2.36% ± 1.36% for ICS,respectively (Fig. 3a), and 8.43% ± 4.78%,4.97% ± 2.64%, and 3.69% ± 2.05% for LABA,respectively (Fig. 3b), showing that significantlyhigher proportions of ICS and LABA weredeposited from Flutiform than from Symbicortand Relvar (p\0.001).

Particle Deposition Imaging of EachProduct in the Upper, Central,and Peripheral Airways

Particle deposition images of ICS and LABAfrom Flutiform, Symbicort, and Relvar in theairway are provided in Fig. 4a, b. In these imagesof airways, red indicates a dense particle depo-sition (6.74E–03% of delivered dose), and blueindicates a sparse particle deposition(1.51E–08% of delivered dose). The colors in thelobes indicate [13.0% (red) and 0% (blue) ofdelivered dose. Values in the Figures representthe particle deposition fractions in the upper,central, and peripheral airways from top tobottom. The ICS/LABA deposition fractions inthe upper airway were 52.53/54.45%, 72.11/74.56%, and 87.22/80.62% for Flutiform, Sym-bicort, and Relvar, respectively, showing thatthe drug deposition fractions in the upper air-way were higher with Symbicort and Relvarthan with Flutiform, with less than 30% of thedose being deposited to the central/peripheralairways. All data in Fig. 4 were from imaging inthe same subject. Drug deposition imaging data

Table 1 continued

R20 ex-in (kPa/(L/s)) 0.06 ± 0.04

R5–R20 ex-in (kPa/(L/s)) -0.01 ± 0.02

X5 ex-in (kPa/(L/s)) 0.00 ± 0.01

Ax ex-in (kPa/L) 0.13 ± 0.21

Fres ex-in (1/s) 4.59 ± 6.22

FRI parametersa

Lung lobar airway resistance (iRaw)

Total (kPa/L) 0.0305 ± 0.0159

Distal (kPa/L) 0.0209 ± 0.0133

Right upper lobe (kPa/L) 0.1001 ± 0.0683

Right middle lobe (kPa/L) 0.1738 ± 0.0881

Right lower lobe (kPa/L) 0.1025 ± 0.0630

Left upper lobe (kPa/L) 0.1050 ± 0.0793

Left lower lobe (kPa/L) 0.0910 ± 0.0664

Lung lobar airway volume (iVaw)

Total (mL) 50.42 ± 12.20

Distal (mL) 11.99 ± 5.27

Right upper lobe (mL) 2.28 ± 0.92

Right middle lobe (mL) 1.08 ± 0.57

Right lower lobe (mL) 3.12 ± 1.46

Left upper lobe (mL) 2.53 ± 1.20

Left lower lobe (mL) 2.98 ± 1.35

IOS impulse oscillometry system, FEV1 forced expiratory volumein 1 s, FVC forced vital capacity, Fres resonant frequency, FRIfunctional respiratory imaginga Mean ± SD

224 Pulm Ther (2017) 3:219–231

of all six subjects are shown in the Figs. S1–6. Inaddition, airway deposition imaging with Sym-bicort at the same inspiratory flow rate (30 L/min) as that for Flutiform revealed a furtherdecreased deposition to the central airway(Fig. S7).

DISCUSSION

The imaging data using FRI model were usednumerical number of monodisperse particle sizeand flow rate, it was suggested that pulmonarydeposition of ICS/LABA was difference betweenclinical practice and FRI data. FRI data wasimportant and interest because less-invasivetechnology.

FRI, which is used to determine alveolarhyperinflation, vascular density, ventilation,aerosol deposition, and bronchodilation inpatients with respiratory disease [7], is a

validated method for measuring airflow distri-bution and aerosol deposition in patients withmild asthma, with high correlation with SPECT/CT [4].

Using FRI, the present study showed thatFlutiform, a FP/FM combination via pMDI,provided significantly greater drug depositionin the peripheral airways than Symbicort, aBUD/FM combination via DPI, and Relvar, aFF/VI combination via DPI. Flutiform alsoprovided significantly greater drug depositionin the entire lung and each lobe of the lungthan Symbicort and Relvar. Even though thepMDI was delivered about 30% to the periph-ery compared to the Symbicort DPI of 19%, theBUD dose delivered is essentially the same forasthma treatment. On the other hand, theparticle deposition fraction in the upper airwaywas only approximately half of the dosedelivered from Flutiform, but approximately

a . ICS

30

25

20

15

10

5

0

* * (%)

Flutiform Symbicort Relvar

Max.75 percentileMedian25 percentileMin.

b . LABA

* * 30

25

20

15

10

5

0

(%)Max.75 percentileMedian25 percentileMin.

Flutiform Symbicort Relvar

Fig. 1 Drug deposition fraction in the peripheral airways. a. ICS, b. LABA. *p\0.001, Z test

Pulm Ther (2017) 3:219–231 225

70–90% of the dose delivered from Symbicortand Relvar, revealing a decreased deposition tothe central/peripheral airways with Symbicortand Relvar.

Since the results with Flutiform were betterthan we assumed compared with the other twodevices, an additional FRI analysis was con-ducted for Spiriva Respimat� (BoehringerIngelheim Japan, Inc.), Long-acting muscarinicantagonist (LAMA) delivered via a soft mistinhaler (SMI), a different inhalation device froma pMDI or a DPI. Data on physical property ofSpiriva Respimat were obtained in six patientsusing ACI, while the same impactor used forFlutiform and Symbicort. The drug depositionfractions in the upper, central, and peripheralairways of Spiriva Respimat in the six subjectswere in the ranges of 41.26–44.28, 13.82–22.64,and 34.61–42.35%, respectively (Fig. S8). And

the mean deposition fractions and SDs of Spir-iva Respimat in the entire lung and theperipheral airways were 57.09% ± 1.20% and39.65% ± 2.84%. Although no statistical analy-sis was performed among the drugs, drugdeposition fraction to the peripheral airwayswas the highest with the SMI, followed by thepMDI and then the DPI, indicating a favorablelung deposition profile of pMDIs as well as SMIs(Fig. S9).

It is said that the efficacy of inhaled drugs forasthma depends on the properties of drug par-ticles [8], and studies in patients with mild tomoderate asthma have shown that pMDIs weremore readily accessible to the peripheral airways[9] because of smaller aerosol particle size andhigher aerosolization efficiency compared withDPIs [10]. In addition, it has been shown thatthe optimal particle size for drug delivery to the

a . ICS

Flutiform Symbicort Relvar

25

20

15

10

5

0

45

40

35

30

* * (%) Max.

75 percentileMedian25 percentileMin.

b . LABA

* *

25

20

15

10

5

0

45

40

35

30

(%)

Flutiform Symbicort Relvar

Max.75 percentileMedian25 percentileMin.

Fig. 2 Drug deposition fraction in the entire lung. a. ICS, b. LABA. *p\0.001, Z test

226 Pulm Ther (2017) 3:219–231

central airway and alveoli is from 0.8 to lessthan 5 lm, because particles smaller than0.8 lm are likely to be excreted in expired air[11], and a study assessing the aerodynamicdiameter and its distribution showed that theproportions of ICS/LABA particles smaller than5 lm at expiratory flow rates of 28.3 and 60.0 L/min were 41.2/39.1% and 43.7/42.1% for Fluti-form, respectively, and 8.2/6.5% and 35.0/30.0% for Symbicort, respectively [12], showingthat the proportions of particles smaller than5 lm were higher with Flutiform than withSymbicort. The differences among the productsin deposition to the entire lung, including theperipheral airways, in the present study may bepartly explained by differences in particle sizedistribution, and Flutiform was verified throughFRI to generate more particles with an effectiveparticle size for deposition to the central/

peripheral airways, regardless of the expiratoryflow rate.

In this study, distribution imaging of eachproduct in the upper, central, and peripheralairways showed that the drug deposition frac-tions in the upper airway were higher withSymbicort and Relvar than with Flutiform. Thestudy is of great significance in that the addi-tional data obtained through imaging supportsthe previous finding of high efficiency of Fluti-form in drug deposition to the peripheral air-ways. In clinical practice, it has been reportedthat Flutiform significantly improved asthmacontrol in Japanese asthma patients withremaining eosinophilic inflammation in theperipheral airways [13].

In addition, the greatest difference betweenDPIs and pMDIs is the required inspiratory flowrate. Given a mean required inspiratory flow rate

a . ICS(%)20

15

10

5

0 RUL RML RLL LUL LLL

Max.75 percentileMedian25 percentileMin.

Flutiform Symbicort Relvar

RUL RML RLL LUL LLL RUL RML RLL LUL LLL

b . LABA

(%)20

15

10

5

0

Max.75 percentileMedian25 percentileMin.

Flutiform Symbicort Relvar

RUL RML RLL LUL LLL RUL RML RLL LUL LLL RUL RML RLL LUL LLL

Fig. 3 Drug deposition fraction in each lobe of the lung. a. ICS, b. LABA. RUL right upper lobe, RML right middle lobe,RLL, right lower lobe, LUL left upper lobe, LLL left lower lobe. *p\0.001, Z test: Flutiform vs Symbicort or Relvar

Pulm Ther (2017) 3:219–231 227

228 Pulm Ther (2017) 3:219–231

of 30 L/min for pMDIs and 60 L/min for DPIs[14], the deposition fractions were measured atan inspiratory flow rate of 30 L/min for Flutiformand 60 L/min for Symbicort and Relvar in thepresent study. Since the usual inspiration rateduring safe breathing is approximately 30 L/min,it is of concern as to whether an asthma patientcan generate the inspiratory flow rate requiredfor a DPI, and Flutiform, a pMDI, may thereforeprovide a potent therapeutic option for variousasthma patients, including those who have dif-ficulty using DPIs.

Limitations

Data of particle size distribution of each drugwere obtained using two different cascadeimpactors; ACI for Flutiform, Symbicort, andSpiriva Respimat, and NGI for Relvar, sincethere were no data available for Relvar usingACI, which might have affected the fine particlefraction of each drug and the deposition data.

Also, imaging data in FRI model in this studywere expressed by numerical number ofmonodisperse particle size and flow rate.

Static volume distribution is a limitation ofFRI technology. Functional residual capacity(FRC) imaging is closer to normal inhalation,but due to use of CT resolution, in order tofurther segment the airways, the TLC model wasused.

CONCLUSIONS

In the present study using FRI, Flutiform, a FP/FM combination via pMDI, was shown to pro-vide significantly higher drug deposition frac-tion to the central/peripheral airways thanSymbicort, a BUD/FM combination via DPI, andRelvar, a FF/VI combination via DPI. It is sug-gested that Flutiform may provide a potenttherapeutic option for various asthma patients,including those who have difficulty using DPIs.

ACKNOWLEDGEMENTS

Sponsorship for this study and article process-ing charges was funded by Kyorin Pharmaceu-tical Co., Ltd. FRI analysis and statisticalanalysis were done by Mebix, Inc. and FluiddaNV. Assistance in the submission of thismanuscript was provided by WILL MedicalCommunications Inc. These assistance wasfunded by Kyorin Pharmaceutical Co., Ltd. Thestudy was performed following the guidelineson Good Publication Practice initiated by theInternational Committee of Medical JournalEditors (ICMJE) criteria.All named authors meet the International

Committee of Medical Journal Editors (ICMJE)criteria for authorship for this manuscript, takeresponsibility for the integrity of the work as awhole, and have given final approval for the ver-sion to be published. All authors had full access toall of the data in this study and take completeresponsibility for the integrity of the data andaccuracyof thedataanalysis.YujiTohdawrote themanuscript and all authors read and approved thefinal manuscript to be published.

Disclosures Yuji Tohda has received speaker’sfees from Kyorin Pharmaceutical and Teijin, andanhonorariumfromtheadvisoryboardsofKyorinPharmaceutical and Teijin. Takashi Iwanaga,Takenori Kozuka, Junko Nakanishi, Koji Yamada,OsamuNishiyama,Hiroyuki Sano, and TakamichiMurakami have no conflicts of interest.

Compliance with Ethics Guidelines Thisstudy was conducted in compliance with the

bFig. 4 Particle deposition imaging of Flutiform, Symbi-cort, and Relvar in the upper, central and peripheralairways in the first patient. a. ICS, b. LABA. In the images,red indicates a dense particle deposition (6.74E–03 lg),and blue indicates a sparse particle deposition(1.51E–08 lg). Note: Since the dose levels of ICS/LABAdiffer among the three products, a drug administered at ahigher dose level provides greater absolute deposition thananother drug with the same particle distribution ratio.Accordingly, it may be necessary to take this into accountfor comparison of drug deposition shown by imaging.Nonetheless, since deposition is classified into 11 colorswith an approximately 450,000-fold difference in deposi-tion between the maximum indicated by red and theminimum indicated by blue, a maximum of twofolddifference in the ICS dose and a maximum of fivefolddifference in the LABA dose among the three productsmay be ignorable for color-based comparison of depositionamong the products

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ethical and scientific principles based on theDeclaration of Helsinki (revised in Fortaleza in2013), the Ethical Guidelines for Medical andHealth Research Involving Human Subjects(enforced on December 22, 2014), the MedicalExposure Guidelines 2006, and related laws andregulations, as well as in accordance with theprotocol approved by the Ethics Committee ofKindai University Faculty of Medicine. For themanagement of conflict of interest, the studywas also conducted in line with the Guidancefor Management of Conflict of Interest (Healthand Labour Sciences Research), the Trans-parency Guideline for the Relation betweenCorporate Activities and Medical Institutions(Japan Pharmaceutical Manufacturers Associa-tion), and the Problems Relating to Investiga-tor-initiated Clinical Trials in Japan andCountermeasures (proposed by the ScienceCouncil of Japan) in such a manner that thestudy results would not be influenced by theinterest of the research funder. While no Japa-nese laws or regulations, including the MedicalService Act, restrict the medical exposure dose,the radiation exposure dose in this study waslower than the exposure limit [volume CT doseindex (CTDIvol) of 25 mGy] specified in theAmerican College of Radiology Guidelines [6],indicating that participation in the study wouldinvolve no health hazards.Prior to enrollmentof patients into the study, written voluntaryconsent was obtained from each subject whoreceived a detailed explanation of the studyfrom the investigator based on an informedconsent form approved by the ethics commit-tee. In addition, a subject identification codewas obtained by entering each subject’s name ina correspondence table to assure anonymity ofsubjects.

Open Access This article is distributed underthe terms of the Creative Commons Attribu-tion-NonCommercial 4.0 International License(http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use,distribution, and reproduction in any medium,provided you give appropriate credit to theoriginal author(s) and the source, provide alink to the Creative Commons license, andindicate if changes were made.

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