Liposomal Cyclosporine A (L-CsA) via Inhalation to Treat Bronchiolitis Obliterans Syndrome: Novel Formulation and Drug-Specific Delivery System Improves Tolerability

Abstract

Purpose Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term benefit after lung transplantation. There is no therapy with demonstrated benefit. As BOS is a T-cell mediated process, cyclosporine A given topically to the airways is a good candidate molecule but is highly insoluble. Characteristics of a liposomal formulation (L-CsA) is compared to a propylene glycol formulation (CsA-PG) are presented here. Methods Retrospective comparison of in vitro data and clinical data from prospective randomized clinical trials. CsA-PG (62.5 mg/mL) dosed 300 mg/5 mL three times weekly was compared to L-CsA (lyophilisate reconstituted with 0.25% saline) in a final concentration of 5 mg/1.25mL or 10 mg/2.5mL per twice daily. CsA-PG was delivered by a Sidestream Disposable nebulizer and use of a Mobilaire compressor; L-CsA was delivered via a PARI investigational eFlowr specifically designed for use with L-CsA. (L-CsA eFlow). Results Pharmacokinetic models predict a constant drug level in the lung with twice daily inhalation of L-CsA as compared to 3-times weekly inhalations of CsA-PG which resulted in high peak and low trough levels. Serum level of L-CsA was 57.42 ± 34.26 ng/mL; trough level was 4-5 ng/mL. Inhalation time was mean 60 min for CsA-PG 300mg, 6-10 min for L-CsA 5mg and 8-13 min for L-CsA 10mg dose. Tolerability data is assessed from 373 patient-month drug exposure to CsA-PG and 1068 patient-month exposure to L-CsA. Premedication was not used with L-CsA, whereas premedication with lidocaine and albuterol was necessary to improve tolerability with CsA-PG. In addition, CsA-PG necessitated incremental titration from 100 mg to 300 mg per inhalation to achieve the target dose; no titration was needed with L-CsA. Reported symptoms were (L-CsA vs CsA-PG): pharyngeal soreness 1% vs. 43%; cough 22% vs. 36%; dyspnea 7% vs. 25%; wheezing 1% vs. 7%; discontinuation due to symptoms caused by aerosol administration 0% vs. 7%. Adherence to investigational therapy (L-CsA vs CsA-PG) was 80% vs 60%. Conclusion L-CsA administered via an L-CsA specific PARI investigational eFlowr nebulizer improved tolerability and adherence compared to CsA-PG, another investigational aerosolized cyclosporine. L-CsA uses lower total dose exposure to achieve constant levels of drug in the airway.