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Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study.

ABSTRACT: This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sputum (primary end-point), pulmonary function tests, health-related quality of life and safety were monitored throughout the study. 60 subjects received ciprofloxacin DPI 32.5 mg and 64 received placebo. Subjects on ciprofloxacin DPI had a significant reduction (p<0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU·g(-1) (range -9.78-5.02 log10 CFU·g(-1))) compared with placebo (-0.27 log10 CFU·g(-1) (range -7.96-5.25 log10 CFU·g(-1))); the counts increased thereafter. In the ciprofloxacin DPI group, 14 (35%) out of 40 subjects reported pathogen eradication at end of treatment versus four (8%) out of 49 in the placebo group (p=0.001). No abnormal safety results were reported and rates of bronchospasm were low. Ciprofloxacin DPI 32.5 mg twice daily for 28 days was well tolerated and achieved significant reductions in total bacterial load compared with placebo in subjects with non-cystic fibrosis bronchiectasis.

SUBMITTER: Wilson R

PROVIDER: S-EPMC3640146 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study.

Wilson Robert R Welte Tobias T Polverino Eva E De Soyza Anthony A Greville Hugh H O'Donnell Anne A Alder Jeff J Reimnitz Peter P Hampel Barbara B

The European respiratory journal 20120927 5

This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sp ...[more]

PMID: 23018904

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Project description:BackgroundOral and intravenous formulations of ciprofloxacin have established efficacy and safety profiles in respiratory infections. A dry powder for inhalation (DPI) that uses Novartis' PulmoSphere™ technology has been developed to deliver high concentrations of ciprofloxacin to the lung with low systemic exposure using a portable and convenient passive dry powder inhaler (Novartis' T-326 inhaler).ObjectivesThe primary objective was to investigate the safety and tolerability of ciprofloxacin DPI in healthy male subjects, with a secondary objective to investigate the pharmacokinetics of ciprofloxacin after ciprofloxacin DPI administration.MethodsThis was a phase I, single-dose, single-site, randomized, single-blind, placebo-controlled, crossover study conducted in the hospital setting. Subjects were followed up for safety for approximately 2 weeks. Six healthy male subjects, aged 27-42 years with no history of pulmonary disease, repeated bronchitis or respiratory allergies were enrolled. In randomized order and separated by a 1-week washout period, subjects inhaled a single dose of ciprofloxacin DPI 32.5 mg or placebo from the T-326 inhaler. Primary safety parameters included vital signs, electrocardiogram, laboratory tests, adverse events and lung function (total specific resistance, thoracic gas volume and forced expiratory volume in 1 s). Plasma concentration-time data were used to calculate pharmacokinetic parameters.ResultsCiprofloxacin DPI was well tolerated with no clinically relevant adverse effects on lung function. Estimates of lung deposition derived from physiology-based pharmacokinetic modelling suggest that approximately 40 % of the total dose of ciprofloxacin DPI reached the trachea/bronchi and alveolar space. Systemic ciprofloxacin was detected soon after inhalation [peak concentration in plasma (C(max)) 56.42 μg/L, median time to C max 0.625 h], but total systemic exposure was minimal (area under the plasma concentration-time curve 354.4 μg·h/L). Terminal elimination half-life (9.5 h), apparent total clearance from plasma after non-intravenous administration (91.7 L/h) and apparent volume of distribution (1,262 L) data suggest that elimination from the respiratory tract was prolonged.ConclusionsIn healthy subjects, ciprofloxacin DPI was well tolerated, delivered ciprofloxacin to the lungs and resulted in minimal systemic exposure, allowing further investigation of its clinical use for the management of specific, chronic infections in pulmonary diseases.

Project description:Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.

Dataset Information

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study.

Publications

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study.

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