FRI deposition results consistently the same as scintigraphy

 

Drug inhalation. It is one of the most important aspects in the day-to-day life of patients with respiratory disease. But equally so of those who make it their life’s work to develop medication and tools to ensure the best drug effect through optimal drug delivery with as an ultimate goal: securing the patient’s best quality of life. Compared to any other way of drug delivery (oral, iv…), it is undeniably the most difficult process. The control you have over the delivery process is small, as the external factors you need to keep into account (such as the way the patient breathes or the patient/disease specific anatomical features of the airways and the lungs), to get the medication to the correct location, are numerous. Nevertheless, if performed well, respiratory drug delivery is extremely effective with a very favourable safety profile concerning side effects.

This implies that the whole process, prior to looking at the drug effect, asks to be analysed and optimized, as a ‘key performance indicator’ of your drug or device. Lung deposition analysis of the drug is the designated tool, where scintigraphy has been the ‘holy grail’ for a long time. It shows, in-vivo, what it is supposed to show and indicates in a two-dimensional image where the drug is going to. It is our experience that deposition analysis is crucial in the earlier development phases to de-risk future and more

Figure 1: Patient’s specific airways coupled to an MDI device. Colours represent the local concentration of deposited particles (red indicating high and green low deposition).

Figure 2: Lung deposition results represented in a scintigraphy-like manner and derived from FRI deposition analysis, comparing test and reference product.

expensive development phases and to maximise good decision making. The pains of doing scintigraphy however, are a major disadvantage. Typically it takes a long time, counted in years, for a scintigraphy study to present the end results, which requires many resources and leads to very high study costs. Apart from that, the radiolabelling of the drug can be a very complex process on its own. The trade-off in cost-benefit and whether to commit doing a scintigraphy clinical trial, is not straightforward.

A known alternative to scintigraphy is FRI (functional respiratory imaging) deposition. The technology that combines HRCT scans and CFD (computational fluid dynamics) calculations, has been used ample times over the past twelve years in deposition studies. Very recently, these results have been collected, scrutinized and compared with scintigraphy data available in the literature for the same drugs/devices in similar populations. It is exciting to say: the results are consistently equivalent. The results of the initial investigation are presented in the table below indicating that for no matter which respiratory disease and, no matter which compound or device, FRI deposition shows the same.

Table 1: Lung deposition results (expressed as percentage of labelled dose (% LD) for FRI deposition and scintigraphy in different disease populations and for different compounds and devices.

Product FRI [%] Scintigraphy [%]
Foster in COPD 28 3 31-34 1,2
Flutiform in Asthma 42 5 41 4
Symbicort in Asthma 23 5 22 6
QVAR in Asthma 54 53 7
iNeb nebulization 45 9 42 8
eFlow nebulization 18 9 17 10
LC Sprint nebulization 9 12 10-15 11
Akita nebulization 34 12 31 11,13

The implications of these findings are profound. Given the low cost (an order of magnitude lower compared to scintigraphy studies) and short time-spans (counted in weeks), the respiratory industry gets the challenging opportunity to investigate an immense amount of deposition scenarios in a uniquely controlled way. It is due to the fact that its processes are structured that patient inclusion becomes obsolete. The benefits of FRI deposition go beyond the price and time. The technology allows three-dimensional, high resolution visualizations of the patient specific lungs and airways where regional deposition can be analysed (on a lobar or airway level) without the need of radiolabelling. Since the three-dimensional representation of deposition in actual patient airways is very intuitive, its applications easily extend to marketing and communication (e.g. towards the regulatory agencies) purposes.

Figure 3: One patient’s specific airways coupled to an MDI device showing the local deposition concentration of two different dosages of a compound.

The technology aims to fill the current knowledge gaps and to improve drug delivery in the best way possible. The knowledge that FRI deposition and scintigraphy are equivalent, is a promising aspect in the respiratory field. The findings will be submitted for publication soon. Having FRI as a cheap and reliable tool will allow drug developers to look at deposition from many more angles compared to the past. This will optimise lung deposition in the future and patients will feel the benefit of having maximum efficacy with a minimal amount of side effect. Nonetheless, development never stops and FLUIDDA will continue its research in this area with the goal to optimise respiratory drug development even further.

Movie 1: One patient’s specific airways coupled to an MDI device showing the transport of particles over time as well as the build-up of the local deposition concentration.

 

References

1. De Maria, R. et al. Foster®: A High-Efficiency Combination Metered Dose Inhaler with Consistent Particle Size Distribution at Alternative Flow Rates. Prod. Ther. 4, (2014).

2. De Backer, W. et al. Lung Deposition of BDP/Formoterol HFA pMDI in Healthy Volunteers, Asthmatic, and COPD Patients. Aerosol Med. Pulm. Drug Deliv. 23, 137–148 (2010).

3. Usmani, O. et al. Lung deposition of extrafine inhaled corticosteroid (ICS)-containing fixed combinations drug in COPD patients using Functional Respiratory Imaging. Respir. Soc. (2018).

4. Kappeler, D. et al. Lung deposition of fluticasone propionate/formoterol administered via a breath-triggered inhaler. Respir. J. 50, PA522 (2017).

5. Iwanaga, T. et al. Aerosol Deposition of Inhaled Corticosteroids/Long-Acting β2-Agonists in the Peripheral Airways of Patients with Asthma Using Functional Respiratory Imaging, a Novel Imaging Technology. Ther. 3, 219–231 (2017).

6. Hirst, P. H., Bacon, R. E., Pitcairn, G. R., Silvasti, M. & Newman, S. P. A comparison of the lung deposition of budesonide from Easyhaler, Turbuhaler and pMDI plus spacer in asthmatic patients. Med. 95, 720–727 (2001).

7. Leach, C. L., Kuehl, P. J., Chand, R. & McDonald, J. D. Respiratory Tract Deposition of HFA-Beclomethasone and HFA-Fluticasone in Asthmatic Patients. Aerosol Med. Pulm. Drug Deliv. 29, 127–133 (2016).

8. Nikander, K., Prince, I., Coughlin, S., Warren, S. & Taylor, G. Mode of Breathing—Tidal or Slow and Deep—through the I-neb Adaptive Aerosol Delivery (AAD) System Affects Lung Deposition of 99mTc-DTPA. Aerosol Med. Pulm. Drug Deliv. 23, S-37 (2010).

9. Hull, D., Black, A. & Vos, W. Use of computational fluid dynamics (CFD) to model aerosol deposition in the lungs of patients with cystic fibrosis. Cyst. Fibros. Soc. (2018).

10. Lenney, W., Edenborough, F., Kho, P. & Kovarik, J. M. Lung deposition of inhaled tobramycin with eFlow rapid/LC Plus jet nebuliser in healthy and cystic fibrosis subjects. Cyst. Fibros. 10, 9–14 (2011).

11. Fischer, A., Stegemann, J., Scheuch, G. & Siekmeier, R. Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials. J. Med. Res. 14 Suppl 4, 71–77 (2009).

12. Munro, S., Main, M. & Vos, W. The application of computational deposition modelling, to study the impact of delivering a model standardised inhalation product using a variety of different delivery platforms to the lungs of IPF patients with varying disease severity. What is best for the patient? Drug Deliv. Lungs (2017).

13. Müllinger, B. et al. Intra-pulmonal deposition of two different tobramycin formulations. Cyst. Fibros. 4, S53 (2005).

†. Data on file

Sorry, comments are closed for this post.