Clofazimine for the treatment of tuberculosis

Shorter (6-9 months), fully oral regimens containing new and repurposed drugs are now the first-choice option for the treatment of drug-resistant tuberculosis (DR-TB). Clofazimine, long used in the treatment of leprosy, is one such repurposed drug that has become a cornerstone of DR-TB treatment and ongoing trials are exploring novel, shorter clofazimine-containing regimens for drug-resistant as well as drug-susceptible tuberculosis. Clofazimine's repurposing was informed by evidence of potent activity against DR-TB strains in vitro and in mice and a treatment-shortening effect in DR-TB patients as part of a multidrug regimen. Clofazimine entered clinical use in the 1950s without the rigorous safety and pharmacokinetic evaluation which is part of modern drug development and current dosing is not evidence-based. Recent studies have begun to characterize clofazimine's exposure-response relationship for safety and efficacy in populations with TB. Despite being better tolerated than some other second-line TB drugs, the extent and impact of adverse effects including skin discolouration and cardiotoxicity are not well understood and together with emergent resistance, may undermine clofazimine use in DR-TB programmes. Furthermore, clofazimine's precise mechanism of action is not well established, as is the genetic basis of clofazimine resistance. In this narrative review, we present an overview of the evidence base underpinning the use and limitations of clofazimine as an antituberculosis drug and discuss advances in the understanding of clofazimine pharmacokinetics, toxicity, and resistance. The unusual pharmacokinetic properties of clofazimine and how these relate to its putative mechanism of action, antituberculosis activity, dosing considerations and adverse effects are highlighted. Finally, we discuss the development of novel riminophenazine analogues as antituberculosis drugs.