Impact of Clofazimine Dosing on Treatment-Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis [PublishAheadOfPrint]

The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment-shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impact of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) six months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when co-administered with first-line drugs continuously throughout treatment, and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcome, an effect that was only evident after the first three months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the anti-tuberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow for the full evaluation of drugs administered in combination over long durations.

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