Safety and efficacy of clofazimine are correlated with its serum concentration: Findings of a prospective observational study for pulmonary nontuberculous mycobacterial disease

<bold>Background:</bold> Although clofazimine (CFZ) has promising effects against pulmonary non-tuberculosis mycobacteria disease (NTM), the appropriate dosage remains unknown. <bold>Objective:</bold> To clarify the relationship between CFZ concentration and its adverse effects and efficacy. <bold>Methods:</bold> This prospective observational study was conducted among NTM patients who were treated with CFZ (UMIN 000041053). The serum trough concentration of CFZ was quantified with validated high-performance liquid chromatography-mass spectrometry. CFZ-induced pigmentation grade, QTc interval, and negative conversion outcomes were analyzed based on measured CFZ serum concentrations by using t-test, concentration-QTc model, and multivariable logistic regression analysis, respectively. <bold>Results:</bold> Out of the 64 enrolled patients, 35 received a CFZ dosage of 50 mg/day and 29 received 100 mg/day. CFZ concentration was higher in patients with more severe pigmentation than in those with less severe pigmentation (P < 0.001). When the CFZ concentration was 1 mg/L, the QTc interval was estimated to be prolonged to 17.3 (95% confidence interval [CI], 3.9–25.4) msec from baseline. Negative conversion was achieved in 33 (51.6%) patients. The significant predictors of negative conversion were surgery (adjusted odds ratio 7.9; 95% CI, 1.4–43.0) and a steady-state CFZ concentration greater than 1 mg/L (adjusted odds ratio 3.3; 95% CI, 1.1–9.9). <bold>Conclusions:</bold> The adverse effects and efficacy of CFZ were related to its serum concentration, and therapeutic drug monitoring may enable the maximization of drug efficacy and minimization of its side effects.