Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Figures & data

Figure 1. The vicious cycle of inflammation and infection and potential therapeutic interventions [9]. Reproduced with permission of the European Respiratory Society ©. Eur J Respir Dis Suppl. 1986; 147: 6–15.

Table 1. The exact prevalence of bronchiectasis is unclear and there are differing reports across the US, Europe and Asia Pacific.

Country	Year	Reported prevalence	Reference
USA	2005	4.2 per 100,000 (age 18–34)	[5]
		271.8 per 100,000 (age >75)
	2012	370 per 100,000 person years	[19]
		537 per 100,000 person years (women, age 80–84)
UK	2004	350.5 per 100,000 (women, age >18)	[18]
		301.2 per 100,000 (men, age >18)
	2013	566.1 per 100,000 (women, age >18)
		485.5 per 100,000 (men, age >18)
Germany	2015	67 per 100,000 person years	[20]
China	2013	135 in 10,811 (age >40)	[17]

Table 2. Ongoing and recent clinical trials of inhaled antibiotics in NCFB.

	RESPIRE 1 and 2 Ciprofloxacin DPI [31,32]	ORBIT 3 and 4 Dual release ciprofloxacin for inhalation [29,30]	AIR-BX 1 and 2 Aztreonam lysine for inhalation [33,34]	Colistin [35]
Geographic regions	Global	Global	Global	UK, Russia and Ukraine
Randomization ratio	2 : 1	2 : 1	1 : 1	1 : 1
Treatment	Ciprofloxacin DPI 32.5 mg (single inhalation) BID vs. placebo BID	Dual release ciprofloxacin for inhalation (150 mg of liposomal ciprofloxacin and 60 mg of free ciprofloxacin) QD vs. placebo QD	Aztreonam lysine for inhalation 75 mg TID vs. placebo TID	Colistin 1 million IU BID vs. placebo BID
Treatment regimen	12 cycles. 14 days on- and 14 days off-drug	6 cycles. 28 days on- and 28 days off-drug	2 cycles. 28 days on therapy followed by 28 days off therapy	Continuous therapy (not cyclical)
	6 cycles. 28 days on- and 28 days off-drug
Formulation	Dry powder (1 capsule)	Nebulized	Nebulied	Nebulized
Total duration of study	48 weeks + 4 weeks	48 weeks + 4 weeks	16 weeks (double-blind)	26 weeks
			28 weeks (total)
Stratification	Pseudomonas aeruginosa infection	Not stated	None	By center
	Macrolide use
	Geographic region
Primary outcome measures	Time to first exacerbation and frequency of exacerbation [Time frame: 48 weeks]	ORBIT 3 – Time to first exacerbation [Time frame: one year] ORBIT 4 – Time to first pulmonary exacerbation [Time frame: 48 weeks]	Change in QOL-B respiratory symptoms score at day 28 [Time frame: baseline to day 28]	The time (days) from baseline/visit 2 (first dose) for each individual patient, until he/she experiences an exacerbation

BID: twice daily dosing; QD: once daily dosing; TID: three times daily dosing; IU: international units.

Box 1. Drug summary

Drug Name	Ciprofloxacin dry powder for inhalation
Phase	III
Indication	NCFB
Mechanism of action	The bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.
Route of administration	Delivery is via an efficient, portable, breath-actuated dry powder inhaler.
Pivotal trial(s)	RESPIRE 1 and RESPIRE 2 [31,32]: largest trial program to be carried out in NCFB to date, with strict entry criteria to ensure enrolled patients represent those who are most likely to benefit from long-term treatment with ciprofloxacin DPI. Two treatment regimens are being studied and patients have been stratified for randomization according to (among other factors) positive culture for P. aeruginosa and/or macrolide use. It is hoped that these studies will provide novel insights into the effectiveness of ciprofloxacin DPI in NCFB patients.

Figure 2. Ciprofloxacin DPI drug and device.

Table 3. Key pharmacokinetic/pharmacodynamics properties of ciprofloxacin DPI in plasma and sputum.

Reference	[46]	[45]	[47]	[48]	[49]		[44]	[50]
Patient population	Mild to moderate COPD	Moderate to severe COPD	Moderate to severe COPD	Moderate to severe COPD	CF		Healthy	CF
Dosing	32.5 mg single dose	32.5 mg twice daily	32.5 mg twice daily	32.5 mg single dose	32.5 mg once daily	65 mg once daily	32.5 mg single dose	32.5 mg single dose	65 mg single dose
Parameter
Plasma
AUC (mg•h/L)	0.715	0.49	0.650 ^a	0.600	0.386	1.38	0.354	0.425	0.995
Cmax (mg/L)	0.115	0.10	0.130 ^a	0.114	0.0896	0.300	0.0564	0.0790	0.182
t½ (h)	7.22	12.2	11.6 ^a	6.00	4.60	5.30	9.538	6.30	8.06
MRT (h)	–	–	–	–	–	–	10.68	6.48	7.27
Sputum
AUC (mg•h/L)	338	295	668	552	–	–	–	89.5	649
Cmax (mg/L)	187	151	310	409	–	–	–	34.9	376
t½ (h)	1.76	–	–	–	–	–	–	7.48	6.19
MRT (h)	–	–	–	–	–	–	–	2.32	3.16

^a There was a single dose on day 12 with BID dosing from day 2 to day 11.

AUC: area under the plasma/sputum concentration–time curve; C_max: maximum drug concentration in plasma/sputum after single dose administration; MRT: mean residence time; t_½: half-life associated with the terminal slope.

Figure 3. Phase II study results: significant reductions in bacterial load were seen for patients treated with ciprofloxacin DPI [55]. Mean bacterial load for the modified intent-to-treat population treated with ciprofloxacin DPI in the Phase II study. Shaded area indicates treatment period (days). Mean reductions in colony forming units at end of therapy were significantly higher ciprofloxacin DPI vs placebo: −3.62 log₁₀ CFU·g⁻¹, range −9.78–5.02 log₁₀ CFU·g⁻¹ vs −0.27 log₁₀ CFU·g⁻¹, range −7.96–5.25 log₁₀ CFU·g⁻¹ *** p = 0.001. Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal May 2013, 41 (5) 1107‐1115; Doi: 10.1183/09031936.00071312.

Figure 4. RESPIRE 1 and 2 treatment regimens [56].

Table 4. Key inclusion and exclusion criteria for the RESPIRE clinical trial program.

Key inclusion criteria

Key exclusion criteria

Stable patients with primary diagnosis of NCFB Idiopathic or post infectious etiology FEV1 <90% and ≥30% predicted ≥2 exacerbations in the previous 12 months Positive culture from an adequate sputum at screening sample for P. aeruginosa, H. influenzae, M. catarrhalis, S. aureus, S. pneumoniae, S. maltophilia or B. cepacia Bronchodilators, anticholinergics, inhaled corticosteroids, or mucolytics, if used as chronic treatment for NCFB, at least for the past 4 weeks prior to screening Macrolides if used as chronic treatment for NCFB for at least 6 months prior to screening

Active allergic bronchopulmonary aspergillosis Active and actively treated nontuberculosis mycobacterial infection or tuberculosis Diagnosis of common variable immunodeficiency Recent significant hemoptysis (≥300 mL or requiring blood transfusion) in the preceding 4 weeks before screening (and during the screening period) Primary diagnosis of chronic obstructive pulmonary disease Systemic or inhaled antibiotic treatment for any indication within 4 weeks prior to the administration of study drug; except for chronic macrolide use Systemic corticosteroids at >10 mg/day prednisolone equivalent for >14 days within 4 weeks prior to the administration of study drug

NCFB: non-cystic fibrosis bronchiectasis; FEV₁: forced expiratory volume in one second.

Table 5. Main end points in the RESPIRE clinical trial program.

Primary efficacy end points Frequency of exacerbations Time to first exacerbation

Secondary efficacy end points

Frequency of exacerbations over 48 weeks/time to first exacerbation within 48 weeks after start of treatment Frequency of pulmonary exacerbation as defined as events with systemic antibiotic use and worsening of at least one sign/symptom Apparent pathogen eradication present at baseline Changes from baseline in the disease-specific PRO score SGRQ (symptoms component score) Occurrence of new pathogens not present at baseline Changes from baseline in the disease-specific PRO score QoL-B respiratory symptom domain Changes from baseline in FEV1 (postbronchodilator spirometry)

PRO: patient-reported outcome; FEV₁: forced expiratory volume in one second; SGRQ: St Georges’ Respiratory Questionnaire; QoL-B: quality of life – bronchiectasis.

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