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Clinical Trial
. 2014 Jun;27(3):178-84.
doi: 10.1089/jamp.2013.1042. Epub 2013 May 13.

Lung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients

T E Corcoran  1 , R Niven, W Verret, S Dilly, B A Johnson
Affiliations
Clinical Trial

Lung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients

T E Corcoran et al. J Aerosol Med Pulm Drug Deliv. 2014 Jun.

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.

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Figures

<b>FIG. 1.</b>
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.
<b>FIG. 2.</b>
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.
<b>FIG. 3.</b>
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.
<b>FIG. 4.</b>
FIG. 4.
Blood concentration versus time profiles of CsA after inhalation. Time was assessed from the end of nebulized delivery. Results are means±SD.
See this image and copyright information in PMC

References

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