Preclinical Studies of Clofazimine Inhalation Suspension: A Novel Formulation for the Treatment of Pulmonary Nontuberculous Mycobacterial Disease

<b><i>Background:</i></b> Clofazimine inhalation suspension is a novel formulation of clofazimine developed as a potential lung-targeted treatment for pulmonary nontuberculous mycobacteria disease. <b><i>Methods:</i></b> Safety and toxicokinetic parameters were assessed in 28-day, repeat-dose studies of up to 3.59 mg/kg/day clofazimine inhalation suspension in 8-week-old Sprague Dawley rats and up to 2.72 mg/kg/day in 5-7-month-old beagle dogs with 56-day recovery periods. A 6-month inhalation toxicity study without recovery was also conducted in beagle dogs, with daily doses up to 2.95 mg/kg for 182 days. <b><i>Results:</i></b> No adverse effects were observed, but minimal to mild nonadverse pulmonary changes were observed in high-dose treatment groups. The no-observed-adverse-effect levels were a sex-averaged 1.78 mg/kg in rats (28 days) and 2.73/2.95 mg/kg in male/female dogs (182 days). Median time to maximum concentration ranged from 6 to 12 hours and 0.5 to 6 hours in the rat and dog studies, respectively. Plasma area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased dose-dependently and exhibited accumulation ratios ≥∼2 in both 28-day studies. Clofazimine concentrations in lung tissue were dose-dependent in all 3. <b><i>Discussion:</i></b> Clofazimine inhalation suspension was well tolerated at doses supporting multifold safety margins for the ongoing phase 3 ICoN-1 study. Lung concentrations exceeded the estimated minimum inhibitory concentration against <i>Mycobacterium avium</i> complex, even after 56 days of recovery.