Lung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00755781.

Keywords: aerosol deposition; inhaled cyclosporine; lung transplant.

Figures

FIG. 1.

Comparing radioactivity and drug dose through NGI studies. Radioactivity is compared with drug mass within each aerosol size range after the nebulization of CsA solution for inhalation with a small amount of added Tc-DTPA. Results are means±SD.

FIG. 2.

Demonstrating the linear relationship between CsA drug mass and radioactivity associated with Tc-DTPA. The correlation between radioactivity and drug mass provides the basis for the performance of deposition scintigraphy studies. Results are means±SD.

FIG. 3.

Deposition scintigraphy images from lung transplant recipients. (A) Subject with lowest pulmonary dose (13.2 mg). (B) Subject with highest pulmonary dose (61.3 mg). (C) A single-lung recipient [3.9 mg (native)/25.7 mg (transplant)]. All images are posterior.

FIG. 4.

Blood concentration versus time profiles of CsA after inhalation. Time was assessed from the end of nebulized delivery. Results are means±SD.