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. 2023 May 5:10:1065072.
doi: 10.3389/fmed.2023.1065072. eCollection 2023.

Modeling of pulmonary deposition of agents of open and fixed dose triple combination therapies through two different low-resistance inhalers in COPD: a pilot study

Tamas Erdelyi  1 , Zsofia Lazar  1 , Árpád Farkas  2 , Peter Furi  2 , Attila Nagy  3 , Veronika Müller  1
Affiliations

Modeling of pulmonary deposition of agents of open and fixed dose triple combination therapies through two different low-resistance inhalers in COPD: a pilot study

Tamas Erdelyi et al. Front Med (Lausanne). .

Abstract

Introduction: Inhalation therapy is a cornerstone of treating patients with chronic obstructive pulmonary disease (COPD). Inhaler devices might influence the effectiveness of inhalation therapy. We aimed to model and compare the deposition of acting agents of an open and a fixed dose combination (FDC) triple therapy and examine their repeatability.

Methods: We recruited control subjects (Controls, n = 17) and patients with stable COPD (S-COPD, n = 13) and those during an acute exacerbation (AE-COPD, n = 12). Standard spirometry was followed by through-device inhalation maneuvers using a pressurized metered dose inhaler (pMDI) and a soft mist inhaler (SMI) to calculate deposition of fixed dose and open triple combination therapies by numerical modeling. Through-device inspiratory vital capacity (IVCd) and peak inspiratory flow (PIFd), as well as inhalation time (tin) and breath hold time (tbh) were used to calculate pulmonary (PD) and extrathoracic deposition (ETD) values. Deposition was calculated from two different inhalation maneuvers.

Results: There was no difference in forced expiratory volume in 1 s (FEV1) between patients (S-COPD: 42 ± 5% vs. AE-COPD: 35 ± 5% predicted). Spiriva® Respimat® showed significantly higher PD and lower ETD values in all COPD patients and Controls compared with the two pMDIs. For Foster® pMDI and Trimbow® pMDI similar PD were observed in Controls, while ETD between Controls and AE-COPD patients did significantly differ. There was no difference between COPD groups regarding the repeatability of calculated deposition values. Ranking the different inhalers by differences between the two deposition values calculated from separate maneuvers, Respimat® produced the smallest inter-measurement differences for PD.

Discussion: Our study is the first to model and compare PD using pMDIs and an SMI as triple combination in COPD. In conclusion, switching from FDC to open triple therapy in cases when adherence to devices is maintanined may contribute to better therapeutic effectiveness in individual cases using low resistance inhalers.

Keywords: COPD; deposition; fixed dose triple therapy; modeling; open triple therapy; repeatability.

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Conflict of interest statement

VM received consultation fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, Berlin Chemie Menarini, Orion Pharma, Novartis, GSK, Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pulmonary deposition (PD). AE-COPD: patients with exacerbated COPD; S-COPD: patients with stable COPD.
Figure 2
Figure 2
Extrathoracic deposition (ETD). AE-COPD: patients with exacerbated COPD; S-COPD: patients with stable COPD.
Figure 3
Figure 3
Bland–Altman analysis of pulmonary deposition (PD). The X-axis represents the mean of the two measurements for PD, while the Y-axis shows the difference of the repeated measurements (first measurement–second measurement). Each dot represents a person. The dashed line shows the average of the difference for all subjects. AE-COPD: patients with exacerbated COPD; LoA, Bland–Altman 95% limits of agreement; Meas, measurement; S-COPD: patients with stable COPD.
Figure 4
Figure 4
Bland–Altman analysis of extrathoracic deposition (ETD). The X-axis represents the mean of the two measurements for ETD, while the Y-axis shows the difference of the repeated measurements (first measurement–second measurement). Each dot represents a person. The dashed line shows the average of the difference for all subjects. AE-COPD: patients with exacerbated COPD; LoA, Bland–Altman 95% limits of agreement; Meas, measurement; S-COPD: patients with stable COPD.
Figure 5
Figure 5
Repeatability sequence summary for the three inhalers regarding PD. (A) Control: healthy volunteers (n = 17); (B) All-COPD: patients with stable and exacerbated COPD (n = 25); (C) S-COPD: patients with stable COPD (n = 13); (D) AE-COPD: patients with exacerbated COPD (n = 12). By each control subject and patient, a rank number between 1 and 3 was associated with each inhaler regarding the magnitude of the difference between the two values for PD, respectively. Rank 1 was given to the device with the lowest difference between the two inspiratory measurements followed by Rank 2 and 3. On the figure, rank numbers are shown by three edges of the axes, and the sum of subjects with a certain rank is indicated on the axes. COPD: chronic obstructive pulmonary disease.
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