Inhaled Liposomal Ciprofloxacin: Once a Day Management of Respiratory Infections


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Bruinenberg P, Blanchard JD, Cipolla DC, Dayton F, Mudumba S, Gonda I.

Respiratory Drug Delivery 2010. Volume 1, 2010: 73-82.

Abstract:

Ciprofloxacin for inhalation (CFI) is an aqueous sustained release formulation of ciprofloxacin in development to manage respiratory infections. The liposomal formulation used in clinical studies demonstrates a 24 month shelf-life at 2-8°C with retention of >99% drug encapsulation and no change in liposome size distribution (mean between 80 to 100 nm). Aerosolization using a Pari LC Sprint® nebulizer has no impact on liposome integrity or vesicle size distribution. The droplet size distribution is characterized by a volume median diameter (VMD) of 3.6 µm and geometric standard deviation (GSD) of 2.3. In healthy subjects, single inhalations of 3, 6, and 9 mL of the 50 mg/mL CFI were safe and well tolerated. Plasma pharmacokinetic (PK) profiles demonstrated sustained release of ciprofloxacin from the liposomes with an absorption-limited plasma half life (t½) of ~ 10.5 hours, compatible with a single daily dosing regimen. Once-daily dosing for 14 days of 6 mL inhaled CFI was well tolerated with no serious adverse events (SAEs) in an open label Phase 2a study (n=22) in adult cystic fibrosis (CF) patients. After 14 days of treatment, there was a mean decrease of 1.43 log10 colony forming units (CFU) in sputum Pseudomonas aeruginosa (PA) density , (p<0.01) and a mean increase in FEV1 of 6.9% from baseline (p=0.04). A 28 day Phase 2a study in non-CF bronchiectasis (BE) patients (n= 36) using 3 or 6 mL once daily CFI demonstrated a mean decrease of 4.0 log10 CFU and 3.5 log10 CFU, respectively, in sputum PA density. The safety and tolerability results together with the significant anti-infective effect indicate that once daily CFI is a promising treatment for management of a variety of severe respiratory infections, with reduced systemic exposure to the antibiotic. A Phase 2b randomized, double blind, placebo-controlled trial in BE is underway to evaluate the efficacy, safety and tolerability of 2 or 3 mL once-daily CFI treatment.

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