Optimal concentration of clofazimine achieves culture conversion with less side effects in MAC-PD, suggests study

CFZ has recently emerged as an active treatment in patients with chronic and debilitating pulmonary diseases due to nontuberculous mycobacteria (NTM), Mycobacterium avium complex-pulmonary disease (MAC-PD) and Mycobacterium abscessus-pulmonary disease (MABS-PD). The optimal dose that provides the best balance between efficacy and safety has not been established. Given the risk of severe side effects, including QT interval prolongation, an established risk factor for cardiac arrhythmias and skin pigmentation, the relationship of CFZ serum concentration with these outcomes is an issue of paramount importance. This is a prospective observational study that aims to establish these relationships, as well as predictors of successful culture conversion-a marker for treatment success.

The study involved 64 patients (34 with MAC-PD and 30 with MABS-PD) who were being treated with CFZ. The main objective of the study was to investigate the relationship that exists between the steady-state concentration of CFZ and its safety and efficacy profile. The safety outcomes measured included the severity of pigmentation and QTc interval prolongation, while the efficacy outcome included culture conversion. Our study used Student's t-test for the analyses of pigmentation grades, a concentration-QTc model for QT interval assessment, and multivariable logistic regression to identify predictors of culture conversion.

Key Findings

Severity of Pigmentation and CFZ Concentration:

• There was a significantly higher CFZ concentration in patients with moderate-to-severe pigmentation compared to those with none-to-light pigmentation (P < 0.001).

• This result shows that the degree of pigmentation, considered one of the significant side effects of the drug, is directly influenced by CFZ concentration.

QT Interval Prolongation:

 • The study also identified that for every 1 mg/L increase in CFZ concentration, the QTc interval increased by an average of 17.3 ms (95% CI, 3.9–25.4) above baseline; therefore, the prolongation represents increased cardiac risk at higher concentrations of CFZ.

Culture Conversion Rates:

• Among the 64 patients, culture conversion-that is, successful treatment-was achieved in 33 patients, or 51.6%.

• In this study, isolated surgery was identified as the only significant predictor of culture conversion (adjusted odds ratio of 5.4, 95% CI 1.3-38.0).

• CFZ concentration and an MIC of CFZ less than 0.25 mg/L were not associated with culture conversion.

Results from this study underline the fragile balance that needs to be achieved with CFZ therapy in patients with MAC-PD and MABS-PD. While higher concentrations of CFZ may be beneficial in their fight against the mycobacterial infection, higher concentrations also present increased risks of pigmentation and QT interval prolongation. The findings indicate that careful monitoring and dosage adjustment of CFZ based on serum concentration could minimize adverse effects with minimal compromise in efficacy. Interestingly, the absence of association between the concentration of CFZ and culture conversion suggests that the highest exposure does not translate into higher clinical benefits, underpinning the concept of individualized dosing strategies.

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