Liposomal Amikacin For Inhalation Research Articles

Amikacin Liposome Inhalation Suspension: A Review in Mycobacterium avium Complex Lung Disease.

Amikacin liposome inhalation suspension (ALIS; Arikayce®) [formerly known as liposomal amikacin for inhalation, or LAI] is a liposomal formulation of the aminoglycoside antibacterial drug amikacin. The ALIS formulation, administered via inhalation following nebulization, is designed to facilitate targeted and localized drug delivery to the lungs while minimizing systemic exposure. Based on the prespecified primary endpoint analysis of the ongoing phase III CONVERT trial, ALIS has been approved in the USA for use as part of a combination antibacterial drug regimen against Mycobacterium avium complex (MAC) lung disease that is treatment refractory (i.e. an active infection present despite ≥ 6 consecutive months of a multidrug regimen) in adult patients who have limited or no alternative treatment options. In the CONVERT trial, once-daily ALIS as an add-on to guidelines-based therapy (GBT) significantly increased the odds of achieving sputum culture conversion by month 6 compared with GBT alone in patients with treatment-refractory MAC lung disease. The addition of ALIS to GBT was associated with an increased risk of respiratory adverse events compared with GBT alone; however, serious adverse events were experienced by a similar proportion of patients in the two treatment groups. In conclusion, although current evidence for efficacy is limited to microbiological outcomes (with clinical benefit yet to be established), available data suggest that ALIS is a useful option for the treatment of patients with MAC lung disease who have not responded to conventional therapy and for whom there are limited or no alternative treatment options available.

Stability and Consistency of Treatment Effect With Liposomal Amikacin for Inhalation (LAI) as Add-on Therapy in Patients With Pulmonary Nontuberculous Mycobacterial (PNTM) Infection

Stability and Consistency of Treatment Effect With Liposomal Amikacin for Inhalation (LAI) as Add-on Therapy in Patients With Pulmonary Nontuberculous Mycobacterial (PNTM) Infection

Pulmonary Deposition and Elimination of Liposomal Amikacin for Inhalation and Effect on Macrophage Function after Administration in Rats.

Pulmonary nontuberculous mycobacterial (PNTM) infections represent a treatment challenge. Liposomal amikacin for inhalation (LAI) is a novel formulation currently in development for the treatment of PNTM infections. The pulmonary deposition and elimination of LAI and its effect on macrophage function were evaluated in a series of preclinical studies in healthy rats. The pulmonary deposition of LAI was evaluated in female rats (n = 76) treated with LAI by nebulizer at 10 mg/kg of body weight per day or 90 mg/kg per day for 27 days, followed by dosing of dually labeled LAI (LAI with a lipid label plus an amikacin label) on day 28 with subsequent lung histological and amikacin analyses. In a separate study for assessment of alveolar macrophage function, rats (n = 180) received daily treatment with LAI at 90 mg/kg per day or 1.5% saline over three 30-day treatment periods followed by 30-day recovery periods; phagocytic and Saccharomyces cerevisiae (yeast) killing capabilities and inflammatory mediator release were assessed at the end of each period. LAI demonstrated equal dose-dependent deposition across all lung lobes and regions. Lipid and amikacin labels showed diffuse extracellular colocalization, followed by macrophage uptake and gradual amikacin elimination. Macrophages demonstrated accumulation of amikacin during treatment periods and nearly complete elimination during recovery periods. No evidence of an inflammatory response was seen. No differences in microsphere uptake or yeast killing were seen between LAI-treated and control macrophages. Neither LAI-treated nor control macrophages demonstrated constitutive inflammatory mediator release; however, both showed normal mediator release on lipopolysaccharide stimulation. LAI is readily taken up by macrophages in healthy rats without compromising macrophage function.

Management of Pseudomonas aeruginosa infection in cystic fibrosis patients using inhaled antibiotics with a focus on nebulized liposomal amikacin.

Pseudomonas aeruginosa (PsA) is a highly prevalent bacterial organism recovered from the lungs of cystic fibrosis (CF) patients and chronic PsA infection is linked to progressive pulmonary function decline. The eradication and treatment of this organism from CF airways is particularly challenging to CF care providers. Aerosolized antibiotics that target PsA help to slow down growth, maintain lung function and reduce the frequency of pulmonary exacerbations. In this review, we discuss the currently available inhaled antibiotics for management of PsA lung infections in CF patients, with a focus on liposomal amikacin for inhalation (LAI). LAI is a unique formulation of amikacin under development that enhances drug delivery and retention in CF airways via drug incorporation into neutral liposomes. Factors such as once-daily dosing, mucus and biofilm penetration and potentially prolonged off-drug periods make LAI a potentially attractive option to manage chronic PsA lung infections in CF patients.

112 Analysis of long-term use of liposomal amikacin for inhalation (LAI) in patients with cystic fibrosis (CF) who have chronic infection from Pseudomonas aeruginosa

Objective Interim analysis to evaluate safety, tolerability, and efficacy of LAI, a novel amikacin formulation, in CF patients with chronic P aeruginosa infection previously treated with LAI or tobramycin inhalation solution (TIS). Methods In the CLEAR-108 trial, patients were randomized 1:1 to 3 treatment cycles (28 days on/28 days off) of LAI 590 mg QD or TIS 300 mg BID via nebulizer, and stratified by age and forced expiratory volume in 1 second (FEV 1 ). Eligible patients completing the CLEAR-108 trial enrolled in CLEAR-110 for up to 12 treatment cycles of LAI 590 mg QD via nebulizer. Results Of 266 patients who completed CLEAR-108, 206 (92 LAI; 114 TIS) enrolled in CLEAR-110 and received at least 1 dose of LAI 590 mg QD. At this data cut, 149 patients had completed ≥1 year (6 cycles) of LAI treatment in CLEAR-110. At the end of the 6th off-treatment cycle, FEV 1 continued to improve above baseline; relative mean change was 1.11% and 3.39% in patients on prior TIS and LAI, respectively. P aeruginosa sputum density reductions were similar regardless of prior treatment. 84.5% of patients on LAI had ≥1 TEAE (mild, 23.8%; moderate, 49.0%). As in CLEAR-108, most AEs were respiratory: the highest frequency occurred in Cycle 1 for patients in CLEAR-110 from the TIS arm (Cycles 1, 6: 21.1%, 8.6%). In the LAI arm, respiratory AEs were 7.6% and 8.9% for Cycles 1 and 6. A complete 2-year data set is expected in 2015. Conclusion LAI provides sustained pulmonary function improvement in CF patients infected with P aeruginosa. LAI has stable safety/tolerability with prolonged exposure. Data from ongoing analyses will deepen understanding of factors impacting patient response.

WS02.3 Randomized, double-blind (DB), placebo-controlled study and open-label (OL) extension of liposomal amikacin for inhalation (LAI) in patients with refractory nontuberculous mycobacterial (NTM) lung disease (LD)

Objective NTM-LD management often requires lengthy multidrug antibiotic regimens (MDARs) and can be complicated by drug toxicity and poor prognosis. Efficacy, safety, and tolerability of LAI, a novel amikacin formulation, were evaluated in refractory NTM-LD. Methods In the 84-day DB phase, eligible patients whose NTM infection was refractory to guideline-based MDARs for ≥6 mo were stratified by presence/absence of CF and Mycobacterium avium complex (MAC) vs M. abscessus infection. Patients were randomized 1:1 to LAI 590 mg QD or placebo via nebulizer added to their ongoing stable MDARs. In the OL phase, eligible patients received LAI 590 mg QD for another 84 days. Efficacy endpoints included change from baseline on the full semi-quantitative scale for mycobacterial culture, NTM culture negativity, and distance walked on the 6-minute walk test (6MWT) up to Day 168. Adverse events were monitored up to Day 196. Results Of 136 screened patients, 90 were randomized (CF 19%, non-CF 81%; MAC 64%, M. abscessus 36%). 54% were aged >60 y; 31%, >40–60 y; 14%, 18–40 y. At end of study, 80 and 59 patients had completed the DB and OL phases, respectively. LAI achieved statistical significance in the clinically important endpoint of culture negativity at Day 84 (LAI vs placebo, mITT population: 11/44 vs 3/45 patients; P = 0.01) and in the 6MWT (LAI vs placebo: 23.90 vs −25.03 m; P = 0.009). Complete study results showing continuation of these trends will be presented. Conclusions Full study results will provide efficacy and safety profiles of LAI QD added to a MDAR. These data will increase understanding of NTM-LD, including shifting NTM-LD management paradigms.

Delivery of aerosolized liposomal amikacin as a novel approach for the treatment of nontuberculous mycobacteria in an experimental model of pulmonary infection.

Pulmonary infections caused by nontuberculous mycobacteria (NTM) are an increasing problem in individuals with chronic lung conditions and current therapies are lacking. We investigated the activity of liposomal amikacin for inhalation (LAI) against NTM in vitro as well as in a murine model of respiratory infection. Macrophage monolayers were infected with three strains of Mycobacterium avium, two strains of Mycobacterium abscessus, and exposed to LAI or free amikacin for 4 days before enumerating bacterial survival. Respiratory infection was established in mice by intranasal inoculation with M. avium and allowing three weeks for the infection to progress. Three different regimens of inhaled LAI were compared to inhaled saline and parenterally administered free amikacin over a 28 day period. Bacteria recovered from the mice were analyzed for acquired resistance to amikacin. In vitro, liposomal amikacin for inhalation was more effective than free amikacin in eliminating both intracellular M. avium and M. abscessus. In vivo, inhaled LAI demonstrated similar effectiveness to a ∼25% higher total dose of parenterally administered amikacin at reducing M. avium in the lungs when compared to inhaled saline. Additionally, there was no acquired resistance to amikacin observed after the treatment regimen. The data suggest that LAI has the potential to be an effective therapy against NTM respiratory infections in humans.

Evaluation of the Pharmacokinetics and Pharmacodynamics of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infections Using Data from Two Phase 2 Clinical Studies

The pharmacokinetic-pharmacodynamic (PK-PD) relationships between serum exposure measures of liposomal amikacin for inhalation (LAI) and the change in pulmonary function test (PFT) measures and number of CFU from baseline were evaluated in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. A dose of 70, 140, 280, or 560 mg of LAI or placebo was administered to CF patients once daily for 28 days. PFTs and sputum samples for microbiology were assessed on days 7, 14, 21, 28, 35 (for log10 CFU), and 56 (for PFTs). Serum, urine, and sputum samples were collected for PK evaluation. The relationships between efficacy endpoints (relative change in forced expiratory volume in 1 s [FEV1 {expressed in liters}] and FEV1% predicted and the absolute change in log10 CFU of P. aeruginosa from baseline) and exposure measures (dose, day 1 area under the curve [AUC], dose/MIC ratio, and day 1 AUC/MIC ratio) and baseline MIC value were assessed. The serum and urine PK data were best fit by a 3-compartment model (lung, serum, and urine) with linear clearance and interoccasional variation on total and renal clearance. Significant univariable relationships between dose or day 1 AUC and the relative change in PFT measures (P≤0.017) or the absolute change in log10 CFU from baseline (P≤0.037) on the study days were identified. Repeated-measures mixed-effects models, which showed dose- and AUC-related improvements for each efficacy endpoint (P≤0.041), predicted the observed data well. The increases in the relative change in FEV1 and FEV1% predicted of 11% and 9.9%, respectively, and a 1.23-log10 CFU reduction per 560 mg of LAI estimated on day 7 were comparable to the observed increases of 10.7% and 10.3%, respectively, and a 1.24-log10 CFU reduction on the same day. The model-estimated PFT effects were predicted to be sustained to day 28. An additional 0.451-log10 CFU reduction (P=0.022) was estimated on day 14 relative to day 7, with a persistence of effect predicted to day 35.