Preservation of post-transplant lung function with aerosol cyclosporin

Abstract

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 o5 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. Rejection of the transplanted lung occurs at a rate exceeding that of most other solid organ allografts. Rejection of the allograft typically results in decreased pulmonary function and requires potent immunosuppressive treatments that predisposes the patient to opportunistic infections. Persistent acute rejection is the primary risk factor for bronchiolitis obliterans (OB), the pathological marker of chronic rejection [1]. Chronic rejection is the leading cause of late mortality in the lung-transplant population with a median survival after a diagnosis of y3 yrs [2,3].The lung offers a unique opportunity for topical immunosuppression and the potential sparing of the significant sideeffects associated with systemic immunosuppressive agents. Aerosol (nebulised) cyclosporin (ACsA) has been studied for use as an adjuvant therapy for refractory acute rejection of the lung allograft. In two small open-label cohort studies, improvements in rejection grade and pulmonary function were noted after initiation of ACsA [4,5]. ACsA was also used to stabilise pulmonary function in subjects suffering from chronic rejection [6].A randomised, double-blind, placebo controlled trial of the prophylactic use ACsA was initiated to determine whether the drug is effective in preventing acute and chronic rejection. A deposition sub-study was later initiated to gage how well the subjects were depositing the study medication in their lungs. Deposition tests were performed on both drug and placebo subjects and both deposited and mock doses were calculated.The authors hypothesised the following: 1) deposited dose would correlate to an improvement in lung function in the drug subjects but that mock dose wo...

Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried cyclosporine A multifunctional particles for dry powder inhalation aerosol delivery

“…[7][8][9] Local pulmonary delivery of CsA as nebulized liquid aerosols in lung transplant patients has been reported. 10,11 The improved response in a lung transplant patient by inhaled nebulized tacrolimus, another important immunosuppressant drug, for successful lung immunosuppression while significantly reducing systemic side effects and improving patient outcomes has been recently reported by the authors' group. 12 A metered-dose inhaler of CsA has been aerosolized in asthmatic patients.…”

Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where?

“…One paediatric case series reported benefit in terms of OCS reduction in three out of five children [108]. Whether in the future nebulised cyclosporin may be beneficial with fewer side-effects is an important unanswered question [109,110].…”

Characterization of a cyclosporine solid dispersion for inhalation

“…A second disadvantage of nebulization of CsA dissolved in propylene glycol is the low deposition effi ciency, which has been reported to be 5.4% to 11.2% of the metered dose, 4 which is consistent with other studies on nebulization. [5][6][7] To obtain a signifi cant improvement in pulmonary function in lung transplant patients with chronic rejection requires a deposition of at least 5 mg CsA in the lower airways (peripheral part of the lung), 1 which can only be achieved by high metered doses. This further underlines the need for more effective formulations for inhalation.…”