Activity of Clofazimine and TBI-166 against Mycobacterium tuberculosis in Different Administration Intervals in Mouse...

Clofazimine (CLO) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising antituberculosis activity in vitro and in animal models and is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacies of CLO and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CLO were dosed at 20 mg/kg daily for 2 weeks, followed by QD (once daily), TIW (thrice weekly), and BIW (twice weekly) for an additional 10 weeks at the same dose level. The bactericidal activities of TBI-166 and clofazimine via QD, TIW, and BIW dosing regimens were determined after treatment. Once-daily administration of CLO and TBI-166 appeared to be more efficacious than the two intermittent dosing regimens. Once-daily administration of TBI-166 increased the bactericidal activity by approximately 1 log₁₀ CFU in the lung and spleen compared with TIW or BIW dosing after 12 weeks of treatment, while once-daily administration of CLO increased the bactericidal activity by 1.27 to 1.90 log₁₀ CFU/lung and by 1.61 to 2.22 log₁₀ CFU/spleen in the BALB/c mouse model compared to the intermittent therapies. The differences between QD and TIW and between QD and BIW were significant (P < 0.05). The data suggest that accumulated total doses correlate with the log₁₀ CFU reductions. Therefore, intermittent administration of TBI-166 and CLO should be further evaluated at the same accumulated total doses in preclinical and clinical studies.