Ciprofloxacin Dry Powder For Inhalation Research Articles

Ciprofloxacin-Loaded Inhalable Formulations against Lower Respiratory Tract Infections: Challenges, Recent Advances, and Future Perspectives.

Inhaled ciprofloxacin (CFX) has been investigated as a treatment for lower respiratory tract infections (LRTIs) associated with cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and bronchiectasis. The challenges in CFX effectiveness for LRTI treatment include poor aqueous solubility and therapy resistance. CFX dry powder for inhalation (DPI) formulations were well-tolerated, showing a remarkable decline in overall bacterial burden compared to a placebo in bronchiectasis patients. Recent research using an inhalable powder combining Pseudomonas phage PEV20 with CFX exhibited a substantial reduction in bacterial density in mouse lungs infected with clinical P. aeruginosa strains and reduced inflammation. Currently, studies suggest that elevated biosynthesis of fatty acids could serve as a potential biomarker for detecting CFX resistance in LRTIs. Furthermore, inhaled CFX has successfully addressed various challenges associated with traditional CFX, including the incapacity to eliminate the pathogen, the recurrence of colonization, and the development of resistance. However, further exploration is needed to address three key unresolved issues: identifying the right patient group, determining the optimal treatment duration, and accurately assessing the risk of antibiotic resistance, with additional multicenter randomized controlled trials suggested to tackle these challenges. Importantly, future investigations will focus on the effectiveness of CFX DPI in bronchiectasis and COPD, aiming to differentiate prognoses between these two conditions. This review underscores the importance of CFX inhalable formulations against LRTIs in preclinical and clinical sectors, their challenges, recent advancements, and future perspectives.

The RESPIRE trials: Two phase III, randomized, multicentre, placebo-controlled trials of Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) in non-cystic fibrosis bronchiectasis

The primary goals of long-term disease management in non-cystic fibrosis bronchiectasis (NCFB) are to reduce the number of exacerbations, and improve quality of life. However, currently no therapies are licensed for this. Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) has potential to be the first long-term intermittent therapy approved to reduce exacerbations in NCFB patients.The RESPIRE programme consists of two international phase III prospective, parallel-group, randomized, double-blinded, multicentre, placebo-controlled trials of the same design. Adult patients with idiopathic or post-infectious NCFB, a history of ≥2 exacerbations in the previous 12months, and positive sputum culture for one of seven pre-specified pathogens, undergo stratified randomization 2:1 to receive twice-daily Ciprofloxacin DPI 32.5mg or placebo using a pocket-sized inhaler in one of two regimens: 28days on/off treatment or 14days on/off treatment. The treatment period is 48weeks plus an 8-week follow-up after the last dose. The primary efficacy endpoints are time to first exacerbation after treatment initiation and frequency of exacerbations using a stringent definition of exacerbation. Secondary endpoints, including frequency of events using different exacerbation definitions, microbiology, quality of life and lung function will also be evaluated.The RESPIRE trials will determine the efficacy and safety of Ciprofloxacin DPI. The strict entry criteria and stratified randomization, the inclusion of two treatment regimens and a stringent definition of exacerbation should clarify the patient population best positioned to benefit from long-term inhaled antibiotic therapy. Additionally RESPIRE will increase understanding of NCFB treatment and could lead to an important new therapy for sufferers.Trial registration: The RESPIRE trials are registered in ClinicalTrials.gov, ID number NCT01764841 (RESPIRE 1; date of registration January 8, 2013) and NCT02106832 (RESPIRE 2; date of registration April 4, 2014).

Baseline therapies for Bronchiectasis (non-CF etiology) vary by country – data from the RESPIRE1 trial of Ciprofloxacin Dry Powder for Inhalation (DPI)

RESPIRE 1, an international Phase III trial, aimed to evaluate if Ciprofloxacin DPI as long-term, intermittent therapy in bronchiectasis patients (non-CF etiology) with ≥2 exacerbations (prior 12 months) and respiratory pathogens reduces exacerbations and improves quality-of-life (QoL). We investigated concomitant treatment use at baseline in different countries.

Efficacy and Tolerability of Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) in Bronchiectasis (Non-CF Etiology): Results From the Phase III RESPIRE 1 Study

Efficacy and Tolerability of Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) in Bronchiectasis (Non-CF Etiology): Results From the Phase III RESPIRE 1 Study

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

ABSTRACTIntroduction: Non-cystic fibrosis bronchiectasis (NCFB) is an increasingly prevalent chronic respiratory disease, characterized by a cycle of infection and inflammation. It is progressive and associated with poor quality of life, increasing healthcare costs and mortality. Inhaled antibiotics offer the potential to decrease long-term bacterial burden and reduce or delay exacerbations which are a key driver of disease progression and healthcare costs. Currently however, no inhaled treatments are approved for the prevention of exacerbations in patients with NCFB.Areas covered: We consider current evidence for inhaled treatment in NCFB and discuss ciprofloxacin dry powder for inhalation (DPI), a novel treatment using PulmoSphere™ technology, delivered via a pocket-sized, breath-actuated inhaler. We also detail the unique features of the ongoing Phase 3 RESPIRE trials for ciprofloxacin DPI.Expert opinion: The simplicity of use and short administration time could make ciprofloxacin DPI an attractive treatment option with potential to reduce the number of exacerbations in patients with NCFB. The RESPIRE studies are the largest carried out in NCFB to date and will provide a benchmark for future trial design. If approved, following successful Phase 3 data, ciprofloxacin DPI has potential for significant use in NCFB due to its good tolerability and low treatment burden.

Ciprofloxacin DPI: a randomised, placebo-controlled, phase IIb efficacy and safety study on cystic fibrosis

BackgroundTreatment of infective bronchitis involving Pseudomonas aeruginosa is a cornerstone of care in patients with cystic fibrosis (CF). This phase IIb, randomised, double-blind, placebo-controlled study assessed the efficacy and safety...

A Comparison of Study Designs of Inhaled Agents in Non-Cystic Fibrosis Bronchiectasis (NCFB): Key Differences in the Phase 3 RESPIRE Trials of Ciprofloxacin Dry Powder for Inhalation (DPI)

SESSION TITLE: Asthma - Bronchiectasis Posters SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: Ciprofloxacin DPI is in development to reduce the frequency of acute exacerbations in patients with NCFB. We compared the study design of the two Ciprofloxacin DPI Phase 3 RESPIRE trials with other Phase 3 study designs from recent or ongoing NCFB trials of inhaled agents. METHODS: Study designs for the Phase 3 RESPIRE trials were obtained from Bayer internal protocols. Comparative Phase 3 study design elements for aztreonam for inhalation (Barker et al., Lancet Respir Med 2014), dual-release ciprofloxacin for inhalation (Clinicaltrials.gov and clinicaltrialsregister.eu), colistin (Haworth et al. AJRCC 2014), and mannitol (Bilton et al. Chest 2013; Bilton et al. Thorax 2014) were extracted from the published literature or online sources. RESULTS: NCFB trials of inhaled agents evaluate the common objective of reducing exacerbations, but study designs show substantial variations. In addition to differences in the agents and formulations/mode of delivery, there are key differences in study design elements among these trials, including entry criteria, pre-defined pathogens, and requirements for protocol-defined exacerbations. The RESPIRE entry criteria require a patient history of ≥2 prior exacerbations/yr and specific baseline pathogens (Pseudomonas aeruginosa or 6 other Gram-positive or Gram-negative respiratory pathogens). Protocol-defined exacerbations in RESPIRE require both initiation of systemic antibiotic therapy and a symptom duration of at least 2 days. Treatment regimens vary widely among NCFB studies, and treatment durations range from 12 to 52 weeks. RESPIRE is the first Phase 3 NCFB development program to test two different treatment cycles: 14 days on/14 days off therapy and 28 days on/28 days off over 48 weeks of treatment. Further, subjects in RESPIRE will be stratified by positive P. aeruginosa culture and chronic macrolide use. CONCLUSIONS: Key study design elements differ among Phase 3 clinical trials of inhaled agents in patients with NCFB. The RESPIRE trials features unique elements that will advance our understanding of NCFB treatment, including a rigorous definition of exacerbation, both 14- and 28-day treatment cycles, inclusion of patients with P. aeruginosa or other relevant pathogens, and stratification for chronic macrolide therapy. CLINICAL IMPLICATIONS: Comparing study design elements will lead to a better understanding of optimal NCFB trial design and improve identification of patients most likely to benefit from inhaled therapies. DISCLOSURE: Anthony De Soyza: Consultant fee, speaker bureau, advisory committee, etc.: Fees from Almirall, AstraZeneca, Bayer, Chiesi, Forest Laboratories, GSK, and Novartis, Grant monies (from industry related sources): AstraZeneca, Gilead, Bayer, Forest Laboratories, and Novartis Elisabeth Operschall: Employee: Nothing else to disclose Tiemo-Joerg Bandel: Employee: Nothing else to disclose Robert Wilson: Consultant fee, speaker bureau, advisory committee, etc.: Bayer for lectures and advisory board memberships The following authors have nothing to disclose: Timothy Aksamit Presentation will involve study designs of inhaled agents for non-cystic fibrosis bronchiectasis. Some of studies have already been published, some are unpublished and ongoing.

Tolerability and Pharmacokinetic Properties of Ciprofloxacin Dry Powder for Inhalation in Patients With Cystic Fibrosis: A Phase I, Randomized, Dose-Escalation Study

BackgroundInhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis (CF) and non-CF bronchiectasis. However, established nebulized preparations impose a substantial time burden on patients. A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphere™ (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience. ObjectiveThis study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF. MethodsA Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years [19–40]), stable pulmonary status, and chronic Pseudomonas aeruginosa colonization. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled. ResultsTwenty-five patients were enrolled (12 men; median age, 29.0 years [range, 19–40 years]; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg · h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t½ in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. ConclusionsCiprofloxacin DPI was well tolerated, especially with respect to lung function, with minimal systemic exposure compared with data from previous studies of oral and intravenous administration, and with no apparent accumulation at steady state. Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected. Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities. Eudra clinical trial identifier: 2006-003690-26.

Inhalation of a Dry Powder Ciprofloxacin Formulation in Healthy Subjects: A Phase I Study

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.

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

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.