Tobramycin powder for inhalation (TOBI Podhaler or TIP) is approved for the treatment of Pseudomonas aeruginosa airway infection in patients with cystic fibrosis (CF). A population pharmacokinetic model for tobramycin inhalation powder (TIP) in CF patients was developed to characterize the effect of covariates including body mass index (BMI) and lung function (forced expiratory volume in 1 s as percent of the predicted value (FEV1% predicted) at baseline) on the serum exposure parameters.A two-compartment model with first-order elimination and first-order absorption was developed. Across a range of baseline demographic values in the study population, the predicted mean values for the maximum (Cmax) and trough (Ctrough) plasma concentrations at steady state were at least 7.5 and 5-fold lower, respectively, than the recommended thresholds for tobramycin toxicity (12 µg/ml for Cmax and 2 µg/ml for Ctrough). This model adequately described the tobramycin serum concentration-time course in CF patients following inhalation of TIP. The results indicate that no BMI- or FEV1-based dose adjustment is needed for use of TIP in CF patients.

BackgroundPrevious aztreonam for inhalation solution (AZLI) studies included patients with cystic fibrosis, Pseudomonas aeruginosa (PA) airway infection, and forced expiratory volume in 1s (FEV1) 25% to 75% predicted. This double-blind, multicenter, randomized, placebo-controlled trial enrolled patients (≥6years) with FEV1>75% predicted.MethodsAZLI 75mg (n=76) or placebo (n=81) was administered 3-times daily for 28days with a 14-day follow-up.ResultsDay 28 treatment effects were 1.8points for CFQ-R-Respiratory Symptoms Scale (95%CI: −2.8, 6.4; p=0.443; primary endpoint); −1.2 for log10 sputum PA colony-forming units (p=0.016; favoring AZLI), and 2.7% for relative FEV1% predicted (p=0.021; favoring AZLI). Treatment effects favoring AZLI were larger for patients with baseline FEV1 <90% predicted compared to ≥90% predicted. AZLI was well-tolerated.ConclusionsEffects on respiratory symptoms were modest; however, FEV1 improvements and bacterial density reductions support a possible role for AZLI in these relatively healthy patients. ClinicalTrials.gov identifier: NCT00712166.

Background: CF patients take many inhaled drugs and thus have a large treatment burden.Dry powder inhalers (DPI) can deliver drugs faster than liquid nebulizers, but have been limited to low-dose asthma drugs.The T-326 DPI delivers a high payload of the novel tobramycin PulmoSphere™ formulation, which was developed to improve the convenience of administration of inhaled tobramycin.Methods: We review the development of TIP™, the PulmoSphere particle engineering process and the key features and benefits of this novel formulation.Results: TIP PulmoSphere particles are produced by spray-drying an emulsionbased feedstock, resulting in small (median diameter: 1.7-2.7 mm) spheroidal, highly porous, sponge-like particles.These characteristics favor dispersibility by minimizing the area of particle-to-particle contact.The T-326 DPI was designed to reduce administration time vs nebulization.In two clinical studies (EAGER and EVOLVE trials), patients with CF 6 years of age with chronic Pseudomonas aeruginosa and airway obstruction (FEV 1 between 25-75% of predicted) were able to use the drug/device combination successfully.Compared to tobramycin inhalation solution via jet nebulizer, the TIP/T-326 Inhaler combination provides about a 3-fold more efficient deposition of tobramycin to the lung, with faster delivery (4-6 vs 15-20 min), no thorough cleaning requirement, and greater convenience.Conclusion: TIP reduces treatment burden and may improve treatment adherence, a key factor for clinical outcomes in CF.Pulmosphere technology may also be applied to other drugs (small molecules, peptides, proteins) with applications in CF.

Introduction: MP-376 is a proprietary formulation of levofloxacin (LVX) for aerosol administration.We characterized LVX serum and sputum exposures in children with CF receiving MP-376.Methods: Medically stable patients with CF aged 6-16 years (FEV1 range 37 to 127% of predicted) were enrolled.Patients received single daily doses or MP-376 of either 180 (n = 7) or 240 mg (n = 20) for 14 days via a customized eFlow nebulizer based on body weight of 22-29 kg and 30 kg, respectively.Repeated serum and sputum samples were collected for LVX concentration on Days 1 and 14.PK analyses were conducted using non-compartmental methods.Results: 25 patients had evaluable data to estimate serum PK parameters on at least one occasion (22 from both days, 3 from Day 1 only).Mean serum AUC (CV%) was 8.1 (77.1) and 9.8 (55.7) mg*h/L and mean serum Cmax (CV%) was 1.2 (81.2) and 1.5 (62.8) mg/L for 180 and 240 mg doses, respectively.Sputum Cmax was highly variable and the mean (CV%) for both doses combined was 3120 (188) mg/L on Day 1 (n = 13).There was no apparent association between total body weight and/or age with LVX serum or sputum exposure.Conclusions: Serum and sputum LVX levels in pediatric CF patients are comparable to those observed following aerosol MP-376 in adult CF patients.Based on these data, children 6 years of age and older and weighing at least 30 kg should receive the same dose as adult CF patients. 89

The airways of patients with cystic fibrosis (CF) are chronically infected with bacteria, which theoretically poses a risk of microbial contamination of inhaler devices.Inhaled dry powder mannitol has been investigated in patients with CF, showing improvement in FEV 1 , evidence of decreasing exacerbations, and no increase in qualitative or quantitative sputum microbial growth over a 6 month period.Mannitol can be used in the microbiology laboratory as a substrate for certain bacteria in vitro, and therefore we investigated the potential risk of bacterial growth on the device after 1 week of twice daily mannitol use.Methods: Eighty-five devices from 34 CF patients (1-3 per patient returned) were analysed for microbial content after 1 week's use.The presence of P. aeruginosa, S. aureus, MRSA, Candida, yeasts, Aspergillus, coliforms, Burkholderia and Stenotrophomonas was determined.Cultures were examined daily during the first week, then weekly until the end of the incubation period for each media.Results: There was no microbiological growth on 82/85 (96.5%) inhalers.Microbiological growth was reported in one device from each of 3 patients (S. aureus and MRSA, Aspergillus, Candida).In all 3 patients, the contaminated device was the first of 3 used, with subsequent inhalers testing negative for growth of pathogens.None of the 3 patients reported an acute pulmonary exacerbation during the 6 month trial period.Conclusions: These data suggest that contamination with CF-specific pathogens is infrequent after 1 week of use of the inhaler, the recommended duration of use.There was no increase in acute pulmonary exacerbation in patients with a contaminated device.

Introduction: Twice daily (b.i.d.) inhalation of TOBI™ (300 mg/5 mL) in a 28-day on/off-dosing regimen has previously proven its safety and efficacy for the treatment of Pseudomonas aeruginosa (P.a.) in CF subjects.This randomized, open label, cross-over study explored the impact of of continuous o.d.(1×300 mg/d) and b.i.d.(2×300 mg/d) treatment of TOBI™ via PARI eFlow™ rapid on pharmacokinetics (PK) after 4 and 8 wks in CF patients chronically infected with P.a.The primary endpoint was serum PK of tobramycin (AUC 0-90 ).Further objectives were safety, change in MIC of P.a. and lung function.Results: 24 of 29 randomized patients completed both treatment regimens, mean age was 19.8 (range: 8-35) yrs.For o.d.treatment, serum levels were 20% higher after 8 wks compared with 4 wks (AUC 0-90 ratio: 1.203, 95% CI: 0.818-1.468)whereas under b.i.d.treatment there was a 40% decrease after 8 wks compared to 4 wks (AUC 0-90 ratio: 0.608, 95% CI: 0.435-10.850).AUC 0-90 of o.d. and b.i.d. after 8 wks did not differ significantly.Overall number of patients reporting an AE was similar among treatment groups: o.d.N = 20 (76.9%) and b.i.d.N = 21 (75.0%).Most common AEs were nasopharyngitis, headache and cough.Three SAEs have been reported (exacerbation, orthostatic dysregulation and aspergillosis), none was considered related to treatment.Conclusion: Results from this study indicate acceptable safety and tolerability of continuous treatment with TOBI™ and justify exposure of larger populations to alternative treatment regimens in future studies.

Introduction: Twice daily (b.i.d.) inhalation of TOBI™ (300 mg/5 mL) in a 28-day on/off-dosing regimen has previously proven its safety and efficacy for the treatment of Pseudomonas aeruginosa (P.a.) in CF subjects.This randomized, open label, cross-over study explored the impact of of continuous o.d.(1×300 mg/d) and b.i.d.(2×300 mg/d) treatment of TOBI™ via PARI eFlow™ rapid on pharmacokinetics (PK) after 4 and 8 wks in CF patients chronically infected with P.a.The primary endpoint was serum PK of tobramycin (AUC 0-90 ).Further objectives were safety, change in MIC of P.a. and lung function.Results: 24 of 29 randomized patients completed both treatment regimens, mean age was 19.8 (range: 8-35) yrs.For o.d.treatment, serum levels were 20% higher after 8 wks compared with 4 wks (AUC 0-90 ratio: 1.203, 95% CI: 0.818-1.468)whereas under b.i.d.treatment there was a 40% decrease after 8 wks compared to 4 wks (AUC 0-90 ratio: 0.608, 95% CI: 0.435-10.850).AUC 0-90 of o.d. and b.i.d. after 8 wks did not differ significantly.Overall number of patients reporting an AE was similar among treatment groups: o.d.N = 20 (76.9%) and b.i.d.N = 21 (75.0%).Most common AEs were nasopharyngitis, headache and cough.Three SAEs have been reported (exacerbation, orthostatic dysregulation and aspergillosis), none was considered related to treatment.Conclusion: Results from this study indicate acceptable safety and tolerability of continuous treatment with TOBI™ and justify exposure of larger populations to alternative treatment regimens in future studies.