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

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease associated with a high mortality and a median survival of 3–5 years [1–3]. Two recently approved oral medicines, pirfenidone (Esbriet®) and nintedanib (Ofev®), slow deterioration in lung function, but are associated with side-effects which limit their tolerability [4]. The inhaled drug delivery route offers the advantage of local deposition, smaller drug dose and reduced systemic exposure [5]. However, while this route is used for the treatment of obstructive airway diseases, it is not known whether inhaled drug delivery is feasible in IPF. The optimal region of the lung for topical drug delivery in IPF is likely to be the distal, subpleural regions [6–8]. It is also anticipated that airway distortion, characterised by traction bronchiectasis, may influence lung airway flow characteristics in IPF [9–11]. Thus, observations in healthy subjects and those with asthma and COPD (where the target of therapy is the proximal airways) cannot easily be extrapolated to IPF. Understanding the relationship between particle deposition and lung penetration is a necessary pre-requisite to the development of future inhaled treatments for IPF.

There are only a few clinical trials of inhaled therapy for IPF that are registered in clinicaltrials.gov. These include re-positioning of approved inhaled therapies for pulmonary hypertension and cough (associated with IPF in some subjects) and inhaled fentanyl (an opioid) for pulmonary rehabilitation. There are two trials of inhaled antifibrotics in IPF; an αvβ6 integrin inhibitor (NCT03069989) and a galectin-3 inhibitor [12]. There are other molecules in development for the treatment of IPF by the oral route, as well as the approved drugs pirfenidone and nintedanib. It is difficult to speculate about their suitability for inhaled delivery as this is influenced by various factors (physico-chemical properties as well as dose to be administered). However, Genoa Pharmaceuticals has completed a $62 million Series A financing round to pursue a Phase 2 clinical trial of Aerodone (inhaled pirfenidone) to treat idiopathic pulmonary fibrosis (IPF).

Particle size and inhalation flow are critical factors in determining the total and regional lung deposition of inhaled aerosols [13]. Using monodisperse aerosols and gamma-scintigraphy Usmani and colleagues showed that airway deposition of technetium-labelled monodisperse particles of aerosolised salbutamol was related to clinical effect in asthmatics [13]. Pharmacokinetics can complement these investigations and assess the relative contribution of pulmonary and gastrointestinal absorbtion in terms of rate of absorption and bioavailability of inhaled drug. The amount of salbutamol eliminated in the urine during the first 30 min after inhalation, represents the fraction of drug delivered solely to the lungs; thus providing a measure of bioavailability through the lung [14, 15]. This method provides a means of verifying data generated by radio-labeled imaging of deposition pattern.

We therefore assessed the effect of particle size and aerosol dispersity of inhaled salbutamol on lung deposition in subjects with IPF and related the resultant lung deposition patterns to the pharmacokinetic profile. In so doing, we critically investigated the viability of developing inhaled therapies for the treatment of IPF.

To the best of our knowledge, this is the first study in subjects with IPF to quantify inhaled drug delivery and to determine the optimal aerosol particle size for inhalation. The development of new treatments for IPF has focussed largely on identifying targets that localise to the peripheral and basal areas of fibrotic honeycomb lung [23, 24]. Both air- and blood-flow are disrupted in these areas [9] posing significant challenges to systemic and inhaled drug delivery. The effectiveness of systemic oral delivery has been confirmed in subjects with IPF with both pirfenidone and nintedanib [25–27]. However, the toxicity of systemic therapy remains a challenge in clinical practice with sizable proportions of patients being unable to tolerate long term therapy with available anti-fibrotic drugs. Specifically, in a real-world setting, retention on pirfenidone requires active management and dose adjustments; in the PASSPORT registry of > 1000 subjects with IPF 31% discontinued pirfenidone over 2 years and this is reduced to 20% by dose reduction [28]. Aerosolised drug delivery may provide an advantageous option in IPF. However, the effectiveness of this route has yet to be proven in fibrotic lung disease.

We have shown that 1.5 μm diameter aerosol particle sizes are able to effectively penetrate to the peripheral areas of the lungs of subjects with IPF. Whereas, 6 μm particles deposit centrally in the throat and proximal airways with less penetration to the lung periphery. Whilst similar findings have been reported in healthy and asthmatic subjects [13, 29], data in subjects with IPF, in whom airway flow characteristics are altered due to significant architectural distortion and traction bronchiectasis, has hitherto been lacking. Our data are novel and indicate that despite the effects of fibrotic destruction of the lung, small particles can penetrate to the distal regions in IPF.

The IPF lung demonstrates heterogeneous distribution of fibrosis with apparently normal areas of alveolar tissue abutting active regions of fibroproliferation and end-stage honeycomb fibrosis. It is plausible that the optimal site of action of any drug is at any of three possible sites; 1) in areas of established fibrosis where pro-fibrotic pathways are active, 2) at the leading edge of fibrosis (the fibroblastic foci) where nascent fibrotic tissue appears to be laid down or 3) within structurally normal lung where treatment may prevent the development of fibrosis. The optimal site for drug delivery may vary, depending on the mode of action of a given drug. Nonetheless, this study describes the effect of particle size and quantifies the relative amount of drug deposited peripherally and distally. Drug developers may use this information to optimise the dose administered and the particle size to ensure that the correct amount reaches the target area of the lung which they consider most important. In addition, knowledge of the likely amount deposited centrally will facilitate the establishment of suitable safety limits based on the pre-clinical toxicology. The necessary next step will be demonstration of pharmacodynamic effects of novel compounds in the lungs following inhaled administration. The data from the TOPICAL study can be used to guide the future development of drugs to effectively deliver inhaled aerosol to the target pathological sites in the lungs of subjects with IPF.

Relationships between pulmonary function parameters and lung PI have been demonstrated in some pulmonary diseases [30, 31], although not asthma [13]. In IPF, we show that there is a relationship between pulmonary function and lung deposition for all particle sizes tested; the lower the FVC, the lower the PI. This suggests that although inhaled drugs should be suitable for all IPF subjects, dose and device will require optimisation to ensure adequate dose is delivered to the lung periphery across all severities of disease.

Experience of inhaled drug delivery in IPF is limited to a few opportunistic studies of N-acetylcysteine [32–34], interferon-gamma (IFN-γ) [35, 36] and heparin [8]. These studies were generally inconclusive as to the utility of inhaled drug delivery in the treatment of IPF due to small numbers of subjects and a lack of clinical or safety benefits. Using lung gamma-scintigraphy, Diaz and colleagues observed that inhaled interferon-gamma, delivered using a ‘smart’ efficient nebuliser system (1.7 μm), penetrated to the lung periphery [35]. Whilst no clinical benefit has been described using inhaled delivery in IPF, these results are encouraging for inhaled drug delivery to subjects with IPF; indicating that IPF subjects tolerate nebulised delivery twice per day for an extended period; and that both small (MW ≤ 1000) and large molecules (MW >> 1000) may be delivered. More recently, novel anti-fibrotic therapies are being developed for IPF that are solely to be delivered by the inhaled route (e.g. [12] and NCT02612051). Understanding the deposition in the lungs and absorption into systemic circulation following inhalation in this specific disease is crucial to success of such novel therapies.

Patient compliance may be an issue with inhaled drugs for IPF, however, studies in COPD have indicated that the durability, ergonomics and ease of use of the delivery device were relevant factors in determining compliance; age and breathlessness did not affect compliance (Chrystyn et al. 2014). Optimising the delivery device for IPF is another area of future research. It may be prudent to develop the new medicine as an integral unit that includes the drug and the device.

The pharmacokinetic (PK) profile of subjects with IPF was generally in agreement with that predicted for healthy subjects [21], indicating that despite their disease, IPF subjects had relatively healthy metabolic function (similar clearance). Cmax was slightly lower in IPF subjects, possibly reflecting a reduced lung surface area for absorption. In contrast, compared to PK data in asthmatics [22], the salbutamol PK profile in subjects with IPF exhibited a ‘flatter’ profile. This difference may reflect potential differences in lung β-agonist receptors rather than differences in elimination of salbutamol, as PK is similar following intravenous dosing of salbutamol in asthmatics and healthy subjects [37]. The rapid appearance of detectable salbutamol in the systemic circulation after an inhaled dose in IPF is encouraging, as it suggests significant lung deposition and absorption. This is supported by the gamma scintigraphy where a PI like that observed in asthmatics was observed. In contrast, the AUC data indicated that the aerosol dispersity was important; monodisperse aerosols (GSD < 1.22) of salbutamol delivered by the STAG device had higher AUC values than the polydisperse (GSD > 1.22) nebuliser and pMDI, This suggests that efforts should be made by device engineers and formulation scientists to achieve a narrower dispersion of the inhaled drug.

Systemic availability of inhaled salbutamol results from both oral (swallowed) and pulmonary (inhaled) absorption [38]. The amount of urinary excretion in the first 30 min following inhaled dosing reflects the relative bioavailability of salbutamol absorbed through the lungs with negligible contribution from the oral route [15, 39–42]. Salbutamol exposure, as reflected by the AUC and total urinary excretion, were lower for the 1.5 μm particles compared to 6 μm particles; suggesting that peripheral deposition may result in lower systemic availability. Our data would suggest an advantage for using a smaller drug particle size in subjects with IPF.

Although, a small number of subjects was studied, clear patterns of lung deposition were observed based on particle size and the method of administration. We chose to study only two particle sizes of salbutamol; however, the 1.5 μm and 6 μm particles bracket the ‘respirable range’ and allowed us to test the optimal particle size by studying particles at either end of this range. We did not accurately modulate the inspiratory flow rate of the IPF subjects, a factor which might be expected to modify deposition, particularly as the monodisperse aerosols were inhaled using three sequential one-litre bolus breaths followed by a 10 s breath-hold pause, whereas the conventional polydisperse nebuliser delivery used continual tidal breathing. Finally, the physico-chemical properties of salbutamol are specific to this molecule and extrapolation to other chemical entities should take this into account.

This study provides important results to guide drug discovery programmes in the future development of inhaled drugs for the treatment of subjects with IPF. The choice of drug particle size diameter, aerosol particle size dispersion, coupled with innovative device technology will be important factors to consider in targeting drug to the distal sites of lung pathology in these subjects. This study confirms the feasibility of inhaled drug delivery in IPF and supports the development of topical therapies for this progressive and ultimately life-shortening disease.