Clofazimine inhalation suspension for the aerosol treatment of pulmonary nontuberculous mycobacterial infections

Abstract

Background: Nontuberculous mycobacteria are recognized as a concern for cystic fibrosis (CF) patients due to increasing disease prevalence and the potential for detrimental effects on pulmonary function and mortality. Current standard of care involves prolonged systemic antibiotics, which often leads to severe side effects and poor treatment outcomes. In this study, we investigated the tolerability and efficacy of a novel inhaled therapeutic in various mouse models of NTM disease. Methods: We developed clofazimine inhalation suspension (CIS), a novel formulation of clofazimine developed for inhaled administration. To determine the efficacy, minimum inhibitory concentrations were evaluated in vitro, and tolerability of CIS was determined in naïve mouse models over various durations. After establishing tolerability, CIS efficacy was tested in in vivo infection models of both Mycobacterium avium and M. abscessus. Lung and plasma clofazimine levels after chronic treatments were evaluated. Results: Clofazimine inhalation suspension demonstrated antimycobacterial activity in vitro, with MIC values between 0.125 and 2 μg/ml for M. avium complex and M. abscessus. Administration into naïve mice showed that CIS was well tolerated at doses up to 28 mg/kg over 28 consecutive treatments. In vivo, CIS was shown to significantly improve bacterial elimination from the lungs of both acute and chronic NTM-infected mouse models compared to negative controls and oral clofazimine administration. Clofazimine concentrations in lung tissue were approximately four times higher than the concentrations achieved by oral dosing. Conclusion: Clofazimine inhalation suspension is a well tolerated and effective novel therapeutic candidate for the treatment of NTM infections in mouse models.

Of tuberculosis and non-tuberculous mycobacterial infections – a comparative analysis of epidemiology, diagnosis and treatment

“…The clofazimine inhalation suspension therapy has been tested in mouse models of M. avium and M. abscessus and proven to be promising, with the drug accumulating at four times more concentration than the oral dosing, in the lungs. This therapy is well tolerated and effective, and now a novel therapeutic candidate for further validation to use in NTM therapy [134].…”

Emerging trends in inhaled drug delivery

“…Dotted line represents increase in dose range accomplished by particle engineering. arising from other routes of administration [52]. Development of new therapies for NTM treatment capitalizes on the decades of research into development of inhaled therapy for tuberculosis [53].…”

“…The liposomes are taken up by infected macrophages and penetrate biofilms sufficiently to treat the infection and improve lung function [ 51 ]. Clofazimine offers a unique potential to intervene in this disease as the drug spontaneously targets macrophages and local delivery as an aerosol obviates systemic side effects arising from other routes of administration [ 52 ]. Development of new therapies for NTM treatment capitalizes on the decades of research into development of inhaled therapy for tuberculosis [ 53 ].…”

Preclinical Models of Nontuberculous Mycobacteria Infection for Early Drug Discovery and Vaccine Research

“…In particular, the efficacy of different drug delivery routes can be investigated. In this respect, several researchers have conducted studies on inhaled antibiotics, which can be delivered to mice by commercially available micro sprayers or adapted inhalation apparatus [ 26 , 42 , 190 ].…”