Clofazimine shows long half-life and strong target coverage in RR-TB patients

Rifampicin-resistant tuberculosis (RR-TB) is a form of TB that requires new treatment strategies. Clofazimine is a key component of the BPaLC regimen (bedaquiline, pretomanid, linezolid, and clofazimine), an investigational combination being studied for RR-TB. Despite its clinical use, clofazimine’s elimination half-life had never been formally characterized in people with tuberculosis, and there was no agreed pharmacokinetic-pharmacodynamic (PK-PD) endpoint for evaluating probability of target attainment (PTA). To address these gaps, Bern-Thomas Nyang’wa and colleagues developed a population pharmacokinetic (PK) model for clofazimine and used it to evaluate exposure and PTA. The team followed 30 RR-TB patients who received daily oral clofazimine at 100 mg, collecting plasma samples at multiple time points that included the period after stopping treatment to capture drug wash-out. The study set out to describe how clofazimine behaves in the body over time and to provide data to support dose optimization and interpretation of efficacy when clofazimine is used as part of combination regimens.

Concentrations of clofazimine in patient plasma were measured using high-performance liquid chromatography-tandem mass spectrometry, and PK modeling was performed using nlmixr2 in R. The data were best described by a two-compartment model with first-order absorption and elimination, with body weight accounted for by allometric scaling. Typical clearance was estimated at 6.84 L/h. Reported exposure metrics included median AUC₀₋₂₄ values of 1.44 mg·h/L at week one and 15.67 mg·h/L at end of treatment. Median trough concentrations were 0 mg/L at baseline and 0.66 mg/L at the end of treatment. Simulations using the 100 mg daily dose indicated ≥90% T>MIC during a dose interval if MICs are 0.5 mg/L or lower. Applying the TB-PRACTECAL Mtb isolates’ MIC distribution, this level of exposure translates into target attainment for over 95% of trial participants. The analysis also confirmed a long terminal half-life of 45 days, while noting that robust clinical PK-PD targets for PTA in combination treatment remain unavailable.

These results provide a clearer picture of how clofazimine behaves in people treated for RR-TB and offer concrete numbers that clinicians and researchers can use when thinking about dosing and drug exposure. Knowing the long terminal half-life (45 days) helps explain why clofazimine can persist in the body after treatment stops, which is important for safety monitoring and for understanding how the drug contributes to combination regimens such as BPaLC. The finding that a 100 mg daily dose achieves ≥90% T>MIC for MICs at or below 0.5 mg/L, and would cover over 95% of isolates in the TB-PRACTECAL distribution, suggests that current dosing provides good target coverage against most clinical isolates. At the same time, the study emphasizes that clear, robust clinical PK-PD targets for PTA when clofazimine is given as part of combination treatment are still lacking. Further investigation is therefore needed to connect these pharmacokinetic findings with clinical outcomes and to refine dose recommendations in combination regimens.