Predictors of therapeutic exposure and pharmacokinetic variability of second-line anti-TB drugs in MDR-TB patients: a retrospective study.

BACKGROUND: Therapeutic drug monitoring (TDM) is increasingly recommended for managing multidrug-resistant tuberculosis (MDR-TB) due to significant interindividual pharmacokinetic variability. However, data on plasma concentration variability and associated patient factors for second-line anti-TB drugs remain limited.

METHODS: We conducted a retrospective observational study including 74 patients with MDR-TB at West China Hospital, Sichuan University, from January 2022 to December 2024. Plasma concentrations of second-line drugs (levofloxacin, cycloserine, clofazimine, bedaquiline, and linezolid) were measured at steady-state. We analyzed therapeutic target attainment rates, evaluated correlations between drug concentrations and patient baseline characteristics, and explored predictors of drug exposure using multivariable linear regression.

RESULTS: Significant interindividual variability in drug exposure was observed across the studied second-line anti-TB drugs. Clofazimine demonstrated the highest therapeutic target attainment (72.7%), while bedaquiline had the lowest (21.1%). For levofloxacin, 29.8% of patients achieved therapeutic concentrations, whereas cycloserine reached target levels in 43.2% of cases. Age was positively correlated with cycloserine concentrations (ρ = 0.328, p = 0.030). Multivariable regression identified age and liver enzymes (ALT and AST) as independent predictors of levofloxacin exposure. Specifically, elevated ALT was associated with lower levofloxacin levels (B = -0.191, 95% CI: -0.337 to -0.045), while elevated AST was linked to higher levels (B = 0.292, 95% CI: 0.080 to 0.503). Linezolid trough concentrations showed a negative correlation with RBC count, and peak concentrations were positively associated with ESR. Additionally, bedaquiline concentrations correlated positively with CRP levels.

CONCLUSION: Our findings highlight substantial pharmacokinetic variability among second-line anti-TB drugs, influenced by patient age, liver function, and systemic inflammation. These results underscore the potential importance of individualized dosing and routine TDM in optimizing drug exposure and minimizing toxicity in patients with MDR-TB.