Clofazimine population pharmacokinetics and target attainment in rifampicin-resistant Tuberculosis patients

Clofazimine is a key component of the BPaLC regimen (bedaquiline, pretomanid, linezolid, and clofazimine), an investigational treatment for rifampicin-resistant tuberculosis (RR-TB). However, clofazimines elimination half-life has never been formally characterized amongst tuberculosis patients and a pharmacokinetic (PK) - pharmacodynamic (PD) endpoint for probability of target attainment (PTA) evaluations is lacking. To support dose optimization and efficacy interpretation, we developed a clofazimine population pharmacokinetic (PK) model and evaluated exposure and PTA. Thirty RR-TB patients received daily oral clofazimine at 100 mg, and plasma samples were collected at multiple time points that covered clofazimine wash-out after treatment completion. Clofazimine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry and PK modeling was performed using nlmixr2 in R. A two-compartment model with first-order absorption and elimination, and body weight allometric scaling best described the data. Typical clearance was 6.84 L/h, median AUC2 was 1.44 mg{middle dot}h/L and 15.67 mg{middle dot}h/L at week one and end of treatment, respectively; and median trough concentration was 0 mg/L and 0.66 mg/L at baseline and end of treatment. Simulations using 100mg daily dose showed [≥]90% T>MIC during a dose interval, provided MICs are 0.5 mg/L or lower. For the TB-PRACTECAL Mtb isolates MIC distribution, this translates into over 95% of the trial participants. We reported clofazimines post-treatment population PK characteristics and confirmed clofazimines long terminal half-life of 45 days. However, robust clinical PK-PD targets for PTA when given as combination treatment remain unavailable and thus further investigation is warranted.