Lung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients.

BACKGROUND: Inhaled cyclosporine (CsA) is being investigated as a prophylaxis for lung transplant rejection. Lung deposition and systemic exposure of nebulized CsA in lung transplant patients was evaluated as part of the Phase 3 cyclosporine inhalation solution (CIS) trial (CYCLIST). METHODS: Ten patients received 300 mg of CIS (62.5 mg/mL CsA in propylene glycol) admixed with 148 MBq of Tc-DTPA (technetium-99m bound to diethylenetriaminepentaacetic acid) administered using a Sidestream(®) disposable jet nebulizer. Deposition was assessed using a dual-headed gamma camera. Blood samples were collected over a 24-hr time period after aerosol dosing and analyzed for CsA levels. A pharmacokinetic analysis of the resulting blood concentration versus time profiles was performed. RESULTS: The average total deposited dose was 53.7 ± 12.7 mg. Average pulmonary dose was 31.8 ± 16.3 mg, and stomach dose averaged 15.5 ± 11.1 mg. Device performance was consistent, with breathing maneuvers influencing dose variation. Predose coaching with five of 10 patients reduced stomach deposition (22.6 ± 11.2 vs. 8.3 ± 5.2 mg; p=0.03). Blood concentrations declined quickly from a maximum of 372 ± 140 ng/mL to 15.3 ± 9.7 ng/mL at 24 hr post dose. Levels of AUC(0-24) [area under the concentration vs. time curve from 0 to 24 hr] averaged 1,493 ± 746 ng hr/mL. On a three times per week dose regimen, this represents <5% of the weekly systemic exposure of twice per day oral administration. CONCLUSIONS: Substantial doses of CsA can be delivered to the lungs of lung transplant patients by inhaled aerosol. Systemic levels are small relative to typical oral CsA administration.

Systemic delivery of atropine sulfate by the MicroDose Dry-Powder Inhaler.

BACKGROUND: Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). METHODS: The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses × 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. RESULTS: A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. CONCLUSIONS: Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.

Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway.

Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption. The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption. Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42% x h( -1) versus 32% x h(-1), p = 0.03). The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.

Aerosol drug delivery in lung transplant recipients.

BACKGROUND: Inhaled drug delivery after lung transplantation provides a unique opportunity for direct treatment of a solid organ transplant. At present, no inhaled therapies are approved for this population though several have received some development. Primary potential applications include inhaled immunosuppressive and anti-infective drugs. OBJECTIVES: The objective of this article is to review potential applications of inhaled medications for lung transplant recipients, the techniques used to develop inhaled drugs and the challenges of aerosol delivery in this specific population. METHODS: The results of relevant studies are reviewed and two developmental examples are presented. RESULTS/CONCLUSIONS: Inhaled medications may provide significant advantages for lung transplant recipients. Past studies with inhaled cyclosporine and amphotericin-B provide useful guidance for clinical development of new preparations.

Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients.

Lung transplant recipients exhibit a high incidence of invasive aspergillosis. The inhalation of lipid complex amphotericin-B (Abelcet; ABLC) offers a possible prophylactic strategy. The goals of this study were to select the optimal nebulizer delivery system for ABLC and to measure deposited aerosol dose in 12 lung transplant recipients. In vitro testing was performed to select a nebulizer delivery system, and an empirical model was used to estimate lung deposition. Estimated pulmonary doses varied by as much as 2-fold between different nebulizers. Aerosol deposition testing was performed in six single and six double lung recipients, each of whom received one 7 mL (35 mg) nebulized dose of Technetium-labeled ABLC using the selected nebulizer. In single lung recipients, the average deposited doses were 3.9 +/- 1.6 mg (mean +/- S.D.) in the allograft versus 2.1 +/- 1.1 mg in the native lung. Double lung recipients deposited on average 2.8 +/- 0.8 mg (left lung) and 4.0 +/- 1.3 mg (right lung). The drug was well distributed throughout the lungs, but delivery to the native lung was in some cases suboptimal. These studies provide an important precursor to studies of the efficacy of inhaled ABLC as a prophylaxis of invasive aspergillosis after lung transplant.

Inhaled delivery of aerosolized cyclosporine.

Aerosolized cyclosporine was the first calcineurin inhibitor to be developed for inhaled administration. Its use as a topical immunosuppressant after lung transplantation is reviewed. Animal studies in transplant and non-transplant models are considered, as is nebulized delivery of the drug, including the results of scintigraphy and pharmacokinetic studies. Open label clinical studies of the drug for the treatment of chronic and acute lung transplant rejection are detailed. Placebo controlled trials for rejection prophylaxis are described and future directions for the drug are considered. Aerosol cyclosporine provides an excellent example of how inhaled aerosol delivery can provide therapeutic concentrations of drug in the lungs while minimizing the side effects associated with high systemic concentrations. In the case of lung transplantation, the drug is delivered directly to the airways, the location of the pathology resulting in most mortality in this population (chronic allograft rejection), maximizing the efficacy of this dose-dependent immunosuppressant.

Preservation of post-transplant lung function with aerosol cyclosporin.

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing > or = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Development of aerosol drug delivery with helium oxygen gas mixtures.

Aerosol drug delivery using helium-oxygen gas mixtures (heliox) is considered in terms of flow physics, atomization, and aerosol mechanics. Theoretical considerations are then related to past studies of the physiological effects of the inhalation of heliox and its potential use as a drug delivery medium. Past clinical trials of heliox investigating this use are reviewed and technical recommendations made for its successful development. It is proposed that improved peripheral lung drug delivery with heliox is highly dependent on proper administration, especially the inclusion of proper reservoir system for the gas.

Computational simulations of airflow in an in vitro model of the pediatric upper airways.

In order to understand mechanisms of gas and aerosol transport in the human respiratory system airflow in the upper airways of a pediatric subject (male aged 5) was calculated using Computational Fluid Dynamic techniques. An in vitro reconstruction of the subject's anatomy was produced from MRI images. Flow fields were solved for steady inhalation at 6.4 and 8 LPM. For validation of the numerical solution, airflow in an adult cadaver based trachea was solved using identical numerical methods. Comparisons were made between experimental results and computational data of the adult model to determine solution validity. It was found that numerical simulations can provide an accurate representation of axial velocities and turbulence intensity. Data on flow resistance, axial velocities, secondary velocity vectors, and turbulent kinetic energy are presented for the pediatric case. Turbulent kinetic energy and axial velocities were heavily dependant on flow rate, whereas turbulence intensity varied less over the flow rates studied. The laryngeal jet from an adult model was compared to the laryngeal jet in the pediatric model based on Tracheal Reynolds number. The pediatric case indicated that children show axial velocities in the laryngeal jet comparable to adults, who have much higher tracheal Reynolds numbers than children due to larger characteristic dimensions. The intensity of turbulence follows a similar trend, with higher turbulent kinetic energy levels in the pediatric model than would be expected from measurements in adults at similar tracheal Reynolds numbers. There was reasonable agreement between the location of flow structures between adults and children, suggesting that an unknown length scale correlation factor could exist that would produce acceptable predictions of pediatric velocimetry based off of adult data sets. A combined scale for turbulent intensity as well may not exist due to the complex nature of turbulence production and dissipation.

Improving drug delivery from medical nebulizers: the effects of increased nebulizer flow rates and reservoirs.

Drug delivery from jet nebulizers can be considered in terms of the dose inhaled and the respirability of that dose. It is proposed that dose respirability and dose per breath can be controlled through specification of the driving gas flowrate, and that the dose inhaled per breath can also be increased through the use of nebulizer reservoirs. When a Hudson Micromist nebulizer was used and assessments of respirability were made utilizing phase Doppler interferometry, it was noted that the portion of the spray mass in droplet sizes of

Inertial deposition effects: a study of aerosol mechanics in the trachea using laser Doppler velocimetry and fluorescent dye.

This study characterizes the axial velocity and axial turbulence intensity patterns noted in the tracheal portion of a cadaver-based throat model at two different steady flow rates (18.1 and 41.1 LPM.) This characterization was performed using Phase Doppler Interferometry (Laser Doppler Velocimetry). Deposition, as assessed qualitatively using fluorescent dye, is related to the position of the laryngeal jet within the trachea. The position of the jet is dependent on the downstream conditions of the model. It is proposed therefore that lung/airway conditions may have important effects on aerosol deposition within the throat. There is no correspondence noted between regions of high axial turbulence intensity and deposition.

Characterization of the laryngeal jet using phase Doppler interferometry.

The purpose of this study was to characterize the effects of the laryngeal jet on inhalation air flows in the trachea, and to extend these ideas to further an understanding of aerosol deposition in this region. Phase Doppler Interferometry was used to characterize axial velocity and turbulence intensity contours in the tracheal section of a cadaver-based larynx-trachea model. An array of 30 measurements was made at each of 6 downstream planes within the tracheal portion of the model (immediately downstream of the larynx, and at 0.5, 1, 2, 3, and 4 diameters further downstream). The flow was characterized for steady state flow at three Reynolds numbers (1250, 1700, and 2800). The Re = 1250 case approximates the inhalation of a 6-year-old child. Reverse flows with significant velocities were noted in the anterior trachea within one diameter downstream of the larynx, for all three flow cases. The cross sectional area of the reverse flow regions was larger for the lower Reynolds number cases. These reverse flows are a consequence of the nearly triangular shape of the lumen between the vocal folds in the larynx and constitute a potential deposition mechanism. High levels of axial turbulence intensity were noted near the anterior/left tracheal walls within one diameter downstream of the larynx. This indicates the potential for deposition due to turbulence in this region. Turbulence levels were still significant after four downstream diameters, indicating the potential for turbulent deposition at positions further downstream, including the bronchial tree where passage diameters are smaller. Contrary to expectations, turbulence levels were approximately 20% higher for the Re = 1250 case compared to the Re = 2800 at the furthest downstream locations (with 99% confidence). This is likely due to the complex nature of the confined jet flow.