Pulmonary drug delivery of clofazimine: A route of administration and pharmacokinetics guided repositioning strategy against drug resistant tuberculosis informed by use for other disease indications.

Current oral therapeutic regime of clofazimine (CFZ) in tuberculosis treatment is limited by poor pharmacokinetics, long t1/2, and especially exposure-related systemic toxicity. This review critically evaluates pulmonary administration as a targeted delivery approach to reduce the dose and improve therapeutic efficacy. From the primarily anti-leprotic indication, CFZ has evolved for the treatment of multidrug-resistant tuberculosis (MDR-TB), nontuberculous mycobacterial (NTM) diseases, small-cell lung cancer, and as an adjunct in therapies targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in cancer patients. Despite broad-spectrum activity, clinical effectiveness is constrained by its poor physicochemical and pharmacokinetic properties. Due to its high lipophilicity, orally administered CFZ has a high volume of distribution (1470 L) and tends to accumulate in fatty tissues, resulting in long times to reach steady-state concentrations, sub-therapeutic drug levels at the infection site, increased risk of systemic toxicity and triggering drug resistance over time. Although novel delivery systems administered through the oral route are also explored extensively, they are inadequate to address the concerns of sustained systemic exposure. Pulmonary delivery enables direct deposition at the diseased site, provides higher local concentrations, and reduces off-target effects. Poor solubility and high lipophilicity are the principal biopharmaceutical disadvantages of CFZ for oral formulation development. However, these properties are advantageous for pulmonary delivery in facilitating prolonged lung retention and reduced dosing frequency. This review evaluates the current advantages and challenges of CFZ inhalation versus oral formulations, discusses their pharmacokinetic profiles, and explores pulmonary macrophage uptake strategies to optimize tuberculosis treatment outcomes.