There are two main aerosol issues regarding the use of inhaled AAT in cystic fibrosis. First, the finite supply of AAT derived from human plasma makes it imperative to use the most efficient delivery system to ensure adequate supplies of this scarce resource for patients. Second, the time burden must be minimized for patients who may already be taking multiple other aerosol drugs. Our data show that the I-neb AAD System addresses both of these issues. The residual dose is very small, and the aerosol is generated only during inspiration, minimizing drug waste. The target inhalation mode directs the patient to inhale slowly to avoid particle impaction in the upper airway, allowing more drug to deposit in the lungs. We speculate that the TIM mode may also result in better distribution of drug in the lower airways due to slower particle velocity and less impaction in the proximal airways.(11,12)
For patients who are able to use the I-neb AAD System in TIM, delivery time is only one-third that of TBM. Actual in vivo
results will vary depending on ability of the subject to inhale slowly and deeply.
It has been previously shown that AAT maintains 93.9% specific activity after nebulization by the I-neb AAD System.(13)
If we assume our estimates of lung dose are correct with the I-neb AAD System, using a loaded dose of 25
mg we expect about 13 to 15
mg of active drug to be deposited in the airways. The few trials of aerosolized AAT in CF suggest that the required dose to neutralize the excess free elastase in CF sputum are higher, such that initial drug volume and/or concentration may need to be increased for clinical dose-ramping studies with the I-neb AAD System.
The early studies used the Prolastin formulation of AAT delivered by jet nebulizers.(4,5)
The loaded doses ranged from 100 to 350
mg delivered twice daily, with estimates of lung doses between 10 to 70
mg (10–20% of loaded dose). When the AAT levels in BAL fluid exceeded 8
μM after treatment, all free elastase in BAL fluid was inhibited. When sputum levels of free elastase are used instead of BAL fluid levels, the results are not as clear.(2)
A pilot study looked at doses of 125, 250, and 500
mg recombinant AAT (PPL Therapeutics, Scotland, UK) delivered by a Pari LC Star®
nebulizer (Pari GmbH, Starnberg, Germany) daily for 4 weeks.(14)
Sputum myeloperoxidase, a surrogate for neutrophil activity, was reduced only in the high-dose group, whereas there was only an insignificant trend toward reduced sputum free elastase and IL-8 levels. In CF, the neutrophils are concentrated in the airways (sampled by sputum), not the alveoli (sampled by BAL), so it may be more challenging to suppress free elastase in the milieu of the CF airways. Alternatively, the differences may be in the way that samples of BAL and sputum are processed.(2)
Breath control devices have been used in other studies with AAT and/or CF subjects. Subsequent to the Brand study on lung deposition versus
inhaled breathing pattern,(7)
system (Inamed GmbH, Gemünden, Germany) was developed and was coupled with commercially available jet nebulizers to control inhalation maneuvers to improve deposition and reduce variability. Based on the patient's lung volume, an individual “smart card” is programmed to determine the inhalation volume, flow, and a breath-holding period, and it also allows for the aerosol to be pulsed during a predetermined portion of the inspiration.(12)
In a group of COPD patients, Brand et al.(15)
compared delivery of AAT with the Akita coupled with jet nebulizers (inspiratory flow 200
mL/sec) versus spontaneous breathing with the LC Star nebulizer or the HaloLite, a first-generation AAD device. The Akita produced a higher total and higher peripheral lung deposition, reduced variability, and delivered drug two to four times faster than the devices using spontaneous breathing.(15)
This finding is remarkably similar to our data from the current study. Another study in CF patients demonstrated that the Akita with LC Star increased drug delivery (cromolyn sodium) and decreased administration time compared to an LC Star with a manual interrupter, again demonstrating the importance of a controlled, slow inhalation.(16)
In an attempt to define the correct airway target for AAT in CF patients, the Akita coupled with jet nebulizers was programmed to deliver 25
mg of AAT to either the lung periphery or the central airways once daily for 4 weeks.(17)
The administration time ranged from 5 to 15
min, depending on patient lung function, which also is in line with our I-neb AAD System data (adjusting for the difference in predicted lung dose). Although there was a reduction in free elastase in sputum, neutrophil counts, and pro-inflammatory cytokines, there was no difference in results between the peripheral versus central deposition groups.(17)
The results indicate that a higher lung dose will be required to completely neutralize free elastase in CF sputum. Longer term clinical trials are needed to determine whether it is necessary to completely eliminate free-elastase activity, or simply reduce it to see a clinical response.
The Akita paired with a jet nebulizer still has the problem of drug waste in the form of a high residual left in the nebulizer. The Akita2 Apixneb®
was developed to solve that problem by coupling Akita technology with a vibrating mesh aerosol generator with a low residual volume. This new system was used in a deposition study for radiolabeled AAT in 20 subjects (healthy, AAT-deficient, or CF).(18)
Inspired flow rate was set to 250
mL/sec, and between 70 and 73% of the nominal dose was deposited in the lungs, regardless of baseline lung function. The amount of time to deliver approximately 50
mg of AAT to the lung ranged between 5 and 15
min for most subjects.(18)
If we extrapolate the I-neb AAD System in TIM-9 data, the estimated time of delivery of 50
mg AAT would be about 8 to 9 minutes, similar to the Akita2 Apixneb study.
The I-neb AAD System and the Akita2 Apixneb both have the capability of delivering large amounts of AAT to the lung in a reasonable time period. They both can control the inhalation pattern and pulse the aerosol in the desired portion of the breath, targeting the lower airways in a precise, reproducible manner. The devices differ in the way they accomplish this goal. The Akita has a compressor that supplies the low airflow and set inspired volume, forcing the patient to breathe in the prescribed manner. The Akita smart card is programmed based on the lung volume of the patient at one point in time. If the patient becomes ill and their lung function declines, the Akita is unable to change unless another smart card is supplied with the new information. On the other hand, the I-neb AAD System uses built-in electronics to continuously monitor the breathing pattern. It coaxes the patient to breathe in a slow, deep fashion through feedback mechanisms, and if the lung function acutely changes, the I-neb AAD System algorithm quickly adjusts to get the best effort possible from the patient at that time. The I-neb AAD System is also battery powered, smaller in size, and portable. These factors and the demonstrated time savings from using the I-neb AAD System with TIM(19)
make this device more convenient to use for CF patients.