Pharmacokinetics of Inhaled Clofazimine Dry Powder in Healthy Mice

Clofazimine (CFZ), an old and highly lipophilic antimycobacterial drug, is a second-line agent for the treatment of multi-drug-resistant tuberculosis (MDR-TB) and has demonstrated antitubercular efficacy when administered to the lung as different inhalation dry powder formulations. While its efficacy has been established, consensus has not been identified regarding the lung dose, pharmacokinetic (PK) properties, and biodistribution following inhalation. This study aimed to establish the biodistribution and inhaled PK of CFZ dry powder inhalation (DPI) formulation after single and multiple doses in healthy mice. Following a single low or high inhaled dose in healthy mice, lung concentrations of CFZ were ~ 20 folds higher than the corresponding plasma concentrations. Administering eight consecutive inhaled doses (twice weekly) maintained high and sustained lung concentrations (28 to 69 times higher than plasma concentrations), remaining significantly above the minimum inhibitory concentration (MIC: 0.6 - 2.0 μg/mL) of the free drug. Notably, CFZ concentrations in the lungs and plasma showed no discernable elimination phase up to four weeks post-dosing, with prolonged retention. Biodistribution studies indicated preferential CFZ retention in lung and spleen tissue following both single and multiple inhaled doses. In conclusion, these results suggest the novel dry powder inhaled CFZ formulation can produce high therapeutic concentration in lung tissues for extended periods of time after single and multiple doses, thereby, underscoring the potential of using inhaled CFZ as the treatment of MDR-TB.