Lung Deposition Analysis of Two Formulations of Fluticasone/Salmeterol
HFA pMDI in Stable Asthma Patients
Jan De Backer1, Cedric Van Holsbeke1, Wim Vos1, Samir Vinchurkar1, Wilfred De Backer2, Juliet Rebello3, Mayuri Mangale3,
Jaideep Gogtay3
1
Fluidda nv, 2Antwerp University Hospital,3 Cipla Ltd.
INTRODUCTION
● Combination therapy consisting of an inhaled corticosteroid (ICS) and an inhaled long-acting beta2-agonist (LABA), counteracting
airway inflammation and smooth muscle dysfunction, respectively, for the treatment of asthma has been well established owing to the
significant individual and synergist benefits with no important disadvantages or adverse interactions.1
● Seretide® Evohaler® (GlaxoSmithKline, UK) is a combination product in a pressurized metered dose inhaler (pMDI) which contains a
LABA; salmeterol xinafoate (SM) and an ICS; fluticasone propionate (FP) (hereafter referred to as the “reference product”).
● Cipla Ltd. India has developed a qualitative and quantitative equivalent inhaler product containing the same combination of SM and
FP in a pMDI containing hydrofluoroalkane HFA (hereafter referred to as the 'test product').
● Functional Respiratory Imaging (FRI), an application based on Computerized Tomography (CT) analysis and Computational Fluid
Dynamics (CFD), is a novel technique which quantifies the airway morphology functionality as well as the lung deposition of inhaled
medications.
Efficacy
● Imaging efficacy
● Both test and reference treatments showed significant changes from baseline (p<0.05) in all the imaging efficacy parameters (i.e.,
iVaw, iSaw and iRaw).
● There were no significant differences observed between the test and reference products for any of the FRI parameters [Table 2 &
Figure 2]
Figure 2: Difference in the effects of the test and reference product
on iVaw and iRawtwo hours post–administration of study drug
Regional iVaw changes [%]
Regional iVaw changes [%]
20
18
16
14
12
10
8
6
4
2
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
AIM
● To evaluate lung deposition and safety of two formulations of fluticasone/salmeterol HFA pMDI (250/25 µg) using FRI in stable
asthma patients.
20
18
16
14
12
10
8
6
4
2
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
-20
iVaw changes 2h after administration after reference product
iVaw changes 2h after administration after test product
METHODS
Regional iVaw changes [%]
Regional iVaw changes [%]
50
45
40
35
30
25
20
15
10
5
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
-50
Study Design
● This was a phase III, randomized, double-blind, double-dummy, two-period, crossover study (Figure 1) in stable asthma patients.
Each subject inhaled either 2 puffs of the test product or the reference product on two separate treatment days in a crossover
manner. Each treatment day was separated by a washout period of 3-7 days (Figure 1)
50
45
40
35
30
25
20
15
10
5
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
-50
Figure 1: Study design
iRaw changes 2h after administration after test product
Table 2: Imaging results for a) changes post treatment for the 'Test' product, b) changespost treatment
for the 'Reference' product
50/500µg; 2 puffs
Follow-up
IMAGING
TESTS
50/500µg;2 puffs
50/500µg; 2 puffs
Test Product + Placebo
of Reference
Test Product + Placebo
of Reference
iVaw [cm3]
Single dose: 1 day
3-7 days
Single dose; 1 day
4-7 days
Visit 2: Treatment
Washout
Visit 3: Treatment
Follow-up
End of study visit
Mean(SD)
Mean(SD)
Mean (SD)
3.72
1.39
2.34
Pre Reference Post Reference
Mean (SD)
(3.36)*
(1.61)**
(2.12)*
Change
Reference
Mean (SD)
Mean (SD)
p value
Change
(Referencetest)†
3.23 (1.82)*
1.03 (1.17)***
2.20 (1.37)*
52.59 (24.10) 55.82 (25.16)
40.72 (18.92) 41.75 (19.26)
11.87 (6.04) 14.07 (6.67)
0.393
0.266
0.698
295.50 (89.34) 315.75 (94.06)
20.25 (12.02)*
0.660
Central 128.03 (32.93) 131.26 (33.92) 3.23 (2.68)*
Distal 162.22 (65.29) 181.32 (74.42) 19.10 (15.73)*
129.95 (34.29) 132.87 (34.53)
2.92 (3.12)*
0.338
165.55 (60.75) 182.87 (64.96)
17.32 (12.00)*
0.587
iRaw [kPas/L] Central
Distal
● Males and females ≥18 years of age
● Diagnosed with stable asthma and treated in accordance with GINA 2014 guidelines.
The patients were considered stable if:
■
There was no change in the subjects current asthma therapy apart from the use of rescue medication (including the use of any
other asthma medication)
■
The subjects' absolute forced expiratory volume in one second (FEV1) measured pre-dose on the 2nd treatment period (Visit 3)
was within ±10% of the pre-dose FEV1 measured on the 1st treatment period (Visit 2)
● Subjects were non-smokers or ex-smokers who had stopped smoking at least 1 year prior to study entry and had an overall smoking
history of <10 pack years.
Change (Test)
290.24 (93.13) 312.57 (103.03) 22.33 (17.37)*
Total
Key inclusion criteria
Post test
51.93 (23.59) 55.66 (25.85)
Total
Central 40.36 (18.26) 41.74 (19.26)
11.58 (6.23) 13.91 (7.61)
Distal
Total
iSaw [cm2]
Pre Test
0.040 (0.024)
0.028 (0.016) –0.012 (0.013)***
0.039 (0.023)
0.025 (0.013)
–0.014 (0.013)*
0.453
0.014 (0.009)
0.012 (0.007) –0.002 (0.003)***
0.013 (0.010)
0.011 (0.007)
–0.00 (0.003)**
0.897
0.026 (0.017)
0.017 (0.011) –0.010 (0.011)**
0.026 (0.017)
0.014 (0.007)
–0.012(0.011)*
0.485
*p < 0.001, **p<0.01, ***p<0.05, †p > 0.05 for all comparisons
Lung deposition
● The test and the reference products were not statistically different for deep lung deposition (distal + peripheral airways) for fluticasone
or salmeterol (Figure 3 and Figure 4).
● There was no significant difference (p=0.897) in the percentage deposition of salmeterol for the reference (18.7±6.6) versus the test
(18.6±5.7) product.
● There were no significant differences (p=0.856) in the percentage deposition of fluticasone for the reference (18.4±6.6) versus the
test (18.2±5.7) product.
Endpoints
● Efficacy assessments
Primary
● Changes in total airway volume (iVaw) and total airway resistance (iRaw)
● The number of deposited particles per pre-defined airway section
Figure 3: Lung deposition estimates for salmeterol and fluticasone for the reference and the test product
Imaging
■
Scans were performed with low dose radiation using the multi-slice CT scanner with 64 receptors (GE VCT Lightspeed), at FRC
and TLC.
■
The CT data for the asthmatic subjects was utilized for constructing computer models which numerically analyzed airway
resistance, and bronchodilation in terms of airway volume and surface area for the test and reference products.
40
Deep lung depostion fluticasone (%)
40
30
20
0
0
● Calculation of FRI parameters
● iVaw and surface area (iSaw) were calculated by extracting three-dimensional airway models from the patient-specific anatomical
images of CT scans.
● iRaw was calculated by performing CFD calculations on these models.
● CFD also assisted in evaluating the behavior of the inhalation medication in the airways and lungs of the specific patient. 2,3
10
Deep lung depostion salmeterol (%)
● Safety assessments
● Incidence of all adverse events
50
Wilcoxon signed rank test with continuity correction (p-value=0.856)
50
Wilcoxon signed rank test with continuity correction (p-value=0.897)
30
Visit 1: Screening
Seq
n=9
uen
ce 2
n=16
End of
study
20
50/500µg;2 puffs
ce 1
uen
Seq
n=7
Reference Product +
Placebo of test
10
Reference Product +
Placebo of test
iRaw changes 2h after administration after reference product
Reference (18.7±6.6)
Test (18.6±5.7)
Reference (18.4±6.6)
Test (18.2±5.7)
Figure 4: Lung deposition of inhaled salmeterol and fluticasone
for the test (a) and the reference (b) product.
Model development
■
The CT images were used to perform functional imaging for accurate three-dimensional (3D) reconstructions of the airway
geometries using a semi-automatic algorithm of the airways.
■
The peripheral airways were studied by comparing the lobar expansion between FRC and TLC scans.
a
b
Simulation Methodology
■
CFD can be defined as the science of solving mathematical flow equations to obtain flow properties throughout the entire domain
of a computer model.
■
These CFD techniques were applied to evaluate the flow through the airways of the lungs to provide information on deposition of
aerosols in 3D lung models.
Bronchodilation Comparison Methodology
■
Changes from baseline in iVaw and iSaw post treatment were compared between the test product and the reference product.
■
The airway models were imported into a meshing program in order to create a high quality computational grid to calculate the
airway resistance (iRaw). For the determination of iRaw of the lower airway, calculations were performed using the same mass
flow rate (25L/min) at the inlet for all models studied.
■
Outlet conditions were derived from the internal mass flow distributions for the individual lobes, based on the volume changes
between the FRC and TLC scans.
SAFETY
● Overall, both study treatments were well-tolerated.
● A total of 18 adverse events were reported in the study.
● One moderately intense serious adverse event (pneumonia), was reported with the test product, however, it was not considered to be
related to the study treatment.
RESULTS
CONCLUSION
Patient Population
● Of the 18 patients screened, 16 were randomized.
● The demographic characteristics at baseline on Visit 1 are as tabulated in Table 1.
● No significant differences were observed for the test versus the reference product with respect to the imaging data and the lung
deposition estimates.
● CFD, is an efficient tool to assess the performance of inhaled medications.
● The data further suggests that the in vivo performance of the test and reference product are likely be comparable.
Table 1: Baseline characteristics
Parameters
Age (years)
Mean (SD)
58.8 (8.70)
Forced Expiratory Volume (FEV1)(L)
2.97 (0.91)
FEV1 % Predicted
104.50 (18.87)
Forced Vital Capacity (FVC) (L)
4.23 (1.25)
FEV1/FVC (%)
70.95 (9.61)
Raw (kPas/L)
0.328 (0.130)
6MWT (m)
605.06 (75.15)
REFERENCES
1. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org/
2. De Backer JW, et al. Radiology 2010; 12:257(3):854–62.
3. Vinchurkar S, et al. Inhalation Toxicology 2012; 24(2):81–8.
Copyright © 2016 Cipla Ltd. All rights reserved.
Poster presented at the IPCRG Congress, May 25 - 28, 2016, Amsterdam, Netherlands.