Lung Deposition and Pharmacokinetics of Nebulized Cyclosporine in Lung Transplant Patients

摘要

>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.