Amikacin Liposome Inhalation Suspension (ALIS) Penetrates Non-tuberculous Mycobacterial Biofilms and Enhances Amikacin Uptake Into Macrophages

Abstract

Non-tuberculous mycobacteria (NTM) cause pulmonary infections in patients with structural lung damage, impaired immunity, or other risk factors. Delivering antibiotics to the sites of these infections is a major hurdle of therapy because pulmonary NTM infections can persist in biofilms or as intracellular infections within macrophages. Inhaled treatments can improve antibiotic delivery into the lungs, but efficient nebulization delivery, distribution throughout the lungs, and penetration into biofilms and macrophages are considerable challenges for this approach. Therefore, we developed amikacin liposome inhalation suspension (ALIS) to overcome these challenges. Nebulization of ALIS has been shown to provide particles within the respirable size range that distribute to both central and peripheral lung compartments in humans. The in vitro and in vivo efficacy of ALIS against NTM has been demonstrated previously. The key mechanistic questions are whether ALIS penetrates NTM biofilms and enhances amikacin uptake into macrophages. We found that ALIS effectively penetrated throughout NTM biofilms and concentration-dependently reduced the number of viable mycobacteria. Additionally, we found that ALIS improved amikacin uptake by ∼4-fold into cultured macrophages compared with free amikacin. In rats, inhaled ALIS increased amikacin concentrations in pulmonary macrophages by 5- to 8-fold at 2, 6, and 24 h post-dose and retained more amikacin at 24 h in airways and lung tissue relative to inhaled free amikacin. Compared to intravenous free amikacin, a standard-of-care therapy for refractory and severe NTM lung disease, ALIS increased the mean area under the concentration-time curve in lung tissue, airways, and macrophages by 42-, 69-, and 274-fold. These data demonstrate that ALIS effectively penetrates NTM biofilms, enhances amikacin uptake into macrophages, both in vitro and in vivo, and retains amikacin within airways and lung tissue. An ongoing Phase III trial, adding ALIS to guideline based therapy, met its primary endpoint of culture conversion by month 6. ALIS represents a promising new treatment approach for patients with refractory NTM lung disease.

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

“…ALIS, the liposomal amikacin formulation, is able to penetrate M. avium biofilms in vitro and concentration-dependently reduce viable cell counts at concentrations ≥ 16 μg/mL [ 18 ]. It was also shown in an in vitro study that ALIS has activity against intracellular mycobacteria, effectively reducing cell counts of M. avium and Mycobacterium abscessus in infected macrophages [ 19 ].…”

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

“…It was demonstrated that the inhalable liposomal formulation could provide efficient aerosolized delivery of liposomal drugs to lung and increase drug exposure in airways and lung with lower doses than used for systemic administration (9). For instance, ARIKAYCE ® , an inhalable liposomal amikacin has been developed and accelerated approved by FDA in 2018 for treating Mycobacterium avium complex lung disease (10).…”

Comparison of Phospholipid-Based Particles for Sustained Release of Ciprofloxacin Following Pulmonary Administration to Bronchiectasis Patients

“…The two formulations differ primarily in their dosing regimen (once daily vs. twice daily), in the presence of free drug in the CDI formulation, in the mass of excipients administered, and in the nature of the delivery system. The CDI formulation may also be able to more effectively target delivery of ciprofloxacin into biofilms or into pulmonary macrophages [6,16,66].…”

“…In the last decade, numerous phospholipidbased formulations have been advanced into the clinic for the pulmonary administration of anti-infectives. These include two formulations that have achieved marketing authorization: TOBI Ò Podhaler TM , a spray-dried dry powder formulation of tobramycin sulfate for the treatment of chronic Pseudomonas aeruginosa infections in cystic fibrosis (CF) patients [1][2][3][4][5], and Arikayce Ò , a liposomal dispersion of amikacin sulfate for the treatment of non-tuberculosis mycobacterial (NTM) infections [6][7][8][9][10].…”