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 patientsreduced 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.
RCT Entities:
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.
Authors: A T Iacono; T E Corcoran; B P Griffith; W F Grgurich; D A Smith; A Zeevi; G C Smaldone; K R McCurry; B A Johnson; J H Dauber Journal: Eur Respir J Date: 2004-03 Impact factor: 16.671
Authors: T E Corcoran; G C Smaldone; J H Dauber; D A Smith; K R McCurry; G J Burckart; A Zeevi; B P Griffith; A T Iacono Journal: Eur Respir J Date: 2004-03 Impact factor: 16.671
Authors: Christiane Knoop; Ingrid Vervier; Philippe Thiry; Marc De Backer; John M Kovarik; Annick Rousseau; Pierre Marquet; Marc Estenne Journal: Transplantation Date: 2003-08-27 Impact factor: 4.939
Authors: Gilbert J Burkart; Gerald C Smaldone; Michael A Eldon; Raman Venkataramanan; James Dauber; Adriana Zeevi; Kenneth McCurry; Teresa P McKaveney; Timothy E Corcoran; Bartley P Griffith; Aldo T Iacono Journal: Pharm Res Date: 2003-02 Impact factor: 4.200
Authors: Temperance R Rowell; Steven L Reeber; Shernita L Lee; Rachel A Harris; Rachel C Nethery; Amy H Herring; Gary L Glish; Robert Tarran Journal: Am J Physiol Lung Cell Mol Physiol Date: 2017-04-20 Impact factor: 5.464