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

Background: Oral administration of clofazimine, an antimicrobial agent with demonstrated in vitro efficacy against nontuberculous mycobacteria (NTM), including Mycobacterium avium complex, requires high dosages to reach minimum inhibitory concentration in the lungs. Clofazimine Inhalation Suspension is a novel formulation designed to offer rapid, targeted drug delivery with prolonged half-life in lung tissues while minimizing systemic toxicities. The objective of this study was to evaluate the pharmacokinetic and safety profiles and proposed dosing regimen of Clofazimine Inhalation Suspension for adjuvant treatment of pulmonary NTM disease. Methods: A proposed dosing regimen consisting of 28 days of once-daily 4 mL Clofazimine Inhalation Suspension (nominal 80 mg clofazimine) via jet nebulizer followed by a 56-day drug-intake holiday was evaluated using: (1) a first-in-human phase 1 study examining safety, tolerability, and plasma pharmacokinetics of single and multiple ascending doses across 30-90 mg of clofazimine, (2) a physiology-based pharmacokinetic model establishing human equivalent dosing based on preclinical, and phase 1 human Clofazimine Inhalation Suspension data along with published oral clofazimine data and generated human lung pharmacokinetic estimates. Results: Human studies showed no safety issues at any dose. In healthy volunteers, treatment was well tolerated, with mild adverse events and no signs of systemic clofazimine deposition in the skin or sclera. Plasma drug levels are anticipated to remain below the previously established safe levels for oral clofazimine. Discussion: Clofazimine Inhalation Suspension demonstrated effective antimicrobial lung concentrations and achievable long-term coverage with potential for less systemic toxicity than oral clofazimine. This novel formulation is an alternative delivery strategy to oral ingestion for pulmonary NTM disease. Further evaluation in the phase 3 ICoN-1 global clinical trial is underway.