Activity of Clofazimine and TBI-166 against Mycobacterium tuberculosis, in different administration intervals in mouse tuberculosis models.

Clofazimine (CFZ) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising anti-tuberculosis activity in vitro and in animal models, 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 efficacy of CFZ and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CFZ were dosed at 20 mg/kg daily for two weeks, followed by QD (once daily), TIW (thrice weekly) and BIW (twice weekly) for 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 CFZ 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 as compared with TIW or BIW dosing after 12 weeks of treatment, while once daily administration of CFZ increased the bactericidal activity by 1.27 to 1.90 log10 CFU/lung and by 1.61 to 2.22 log10 CFU/spleen in BALB/c mouse model, as compared to the intermittent therapies. The difference between QD and TIW and between QD and BIW were significant (P<0.05). The data suggest that accumulated total doses are correlated to the log10 CFU reductions. Therefore intermittent administration of TBI-166 and CFZ should be further evaluated at the same accumulated total doses in preclinical and clinical studies.