Pharmacokinetic and Pharmacodynamics of Clofazimine Nano-in-Microparticles: Enhanced Brain Delivery and CNS Tuberculosis Amelioration via Intranasal Administration.

Abstract

Mycobacterium tuberculosis (Mtb) demonstrates a proclivity for infecting extrapulmonary sites, notably the brain. Treating these extrapulmonary tuberculosis (TB) manifestations is challenging due to the difficulty of drug delivery across the blood-brain barrier. Clofazimine (CLF) has exhibited promising activity against Mtb, including multidrug-resistant variants, in vitro and in preclinical animal models. However, its clinical implication is restricted owing to poor physicochemical and pharmacokinetic properties. This study aims to develop CLF nano-in-microparticles (CLF-NIMs) for brain drug delivery for central nervous system TB (CNS-TB) treatment via the intranasal route. Simultaneously, the potential dissemination of TB bacilli to the brain was investigated. Following treatment, colony-forming unit (CFU) enumeration was conducted in both the brain and lung tissues to assess mycobacterial burden. Concurrently, drug concentrations were quantified in serum, brain, and lung tissue, enabling a comprehensive evaluation of pharmacokinetics and tissue-specific drug distribution. In pharmacokinetic investigations of CLF-NIMs, significant accumulation of CLF was observed in brain tissue compared to orally administered CLF, surpassing the minimum inhibitory concentration of CLF. In a murine CNS-TB model, intranasal insufflation of CLF-NIMs for 4 weeks led to a substantial reduction (∼0.99 ± 0.57 Log10CFU/gram) in CFU count in the brain compared to oral administration of CLF (2.45 ± 0.47 Log10CFU/gram). These promising preclinical results indicate that CLF-NIMs are well-tolerated and exhibit significant anti-TB activity in a murine CNS-TB model.