The topical study of inhaled drug (salbutamol) delivery in idiopathic pulmonary fibrosis

Abstract

Background: Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF).

Methods: The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99mTechnetium-labelled monodisperse salbutamol (1.5 μm or 6 μm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 μg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4).

Results: Small monodisperse particles (1.5 μm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 μm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 μm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 μm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 μm and 6 μm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation.

Conclusion: Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF.

Trial registration: This trial was registered on clinicaltrials.gov ( NCT01457261 ).

Keywords: Gamma scintigraphy; Idiopathic pulmonary fibrosis (IPF); Inhaled drug delivery.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the London-Chelsea research ethics committee (11/LO/0372). All subjects provided signed informed consent.

Consent for publication

The institutional consent form was used to cover publication of individual images.

Competing interests

TMM has received industry-academic funding from GlaxoSmithKline R&D, UCB and Novartis and has received consultancy or speaker’s fees from Apellis, Astra Zeneca, aTyr pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, GlaxoSmithKline R&D, InterMune, ProMetic, Roche, Sanofi-Aventis, and UCB. OSU has received industry-academic funding from Boehringer Ingelheim, Chiesi, Edmond Pharma, GlaxoSmithKline, Mundipharma International, and has received consultancy or speaker fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, Cipla, Edmond Pharma, GlaxoSmithKline, Napp, Novartis, Mundipharma International, Pearl Therapeutics, Roche, Sandoz, Takeda, UCB, Vectura and Zentiva. MFB has received industry-academic funding from Boehringer Ingelheim, Chiesi, and GlaxoSmithKline. PTL, RPM, SY, JKS, EO and WAF are employees and shareholders of GlaxoSmithKline R&D.

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Figures

Fig. 1

TOPICAL study design. Subjects were randomised to receive either 1.5 or 6 μm 99mTechnetium labelled monodisperse salbutamol (50 μg) aerosolised using a spinning disk aerosol generator (STAG) in periods 1 and 2. In period 3, all subjects received 99mTechnetium labelled salbutamol using a commercially available nebuliser. In period 4, all subjects received unlabelled salbutamol via a pressurized metered dose inhaler (pMDI). In all periods, charcoal block was administered prior to dosing with salbutamol

Fig. 2

Lung Deposition Images from a representative IPF subject. Anterior thorax γ-camera images of aerosol deposition using technetium-99m–labelled salbutamol particles of 1.5 μm, 6 μm mass median aerodynamic diameter (MMAD) using STAG or using a standard nebuliser. Red areas indicate regions of highest radioactivity and black of least radioactivity

Fig. 3

Lung Deposition and penetration Index. (a) percentage of total dose deposited in the lungs (blue), throat (red hashed), mediastinum (red striped), stomach (pink), exhaled (green) and left in the mouthpiece (blue hashed) for each delivery method (STAG 1.5 μm and 6 μm and nebuliser). (b) Box and whisker plot of lung penetration index. Lung penetration index is illustrated for subjects inhaling the 1.5 μm particle size, the 6 μm particle size and the nebulised salbutamol. Mean (x), median (-), interquartile range (boxes) and outliers (grey spot: subject TOP0008) are shown

Fig. 4

Relationship between pulmonary function and penetration index. Scatter plots of the relationship between FVC (L) and penetration index (PI) for: (a) 1.5 μm particle size (STAG), rho = 0.66667 p = 0.07099; (b) 6 μm particle size (STAG) rho = 0.59524 p = 0.11953; (c) nebulised rho = 0.92857 p = 0.00086. Linear regression analysis (line) is illustrated with its equation. FVC L: forced vital capacity in litres; rho: Spearman Rank Correlation Coefficient

Fig. 5

Plasma salbutamol concentrations. (a) Dose normalised plasma salbutamol concentration per treatment group. Treatment group 1.5 μm salbutamol 50 μg delivered by the STAG device (■), 6 μm salbutamol 50 μg delivered by the STAG device (●), nebulised 2.5 mg salbutamol (▲), 400 μg salbutamol delivered by the pMDI plus spacer (◊). (b) Plasma salbutamol concentration delivered by pMDI plus spacer. Individual subject PK profiles (○) and observed geometric mean PK profile (blue line) for the IPF subjects. Predicted PK profile from asthmatics (red line) [21], predicted PK for healthy subjects (green line) [20]