The need for systematic therapeutic drug monitoring of isoniazid in tuberculosis, a real-world study.

OBJECTIVES: Isoniazid is a primary first-line antituberculosis agent, exhibiting concentration-dependent bactericidal effect while also posing a risk of hepatotoxicity. Therapeutic drug monitoring (TDM) could optimize exposure but remains underused. This study aimed to assess isoniazid pharmacokinetic variability in real-world settings and the proportion of patients achieving therapeutic concentrations. METHODS: We conducted a retrospective, single-center study of adult tuberculosis patients receiving standard first-line therapy (isoniazid, rifampicin, pyrazinamide, ethambutol). Patients underwent fasted-state isoniazid monitoring via a 4-point limited-sampling protocol. We calculated AUC₀₋₂₄ₕ and acetylation status (rapid: half-life <2.2 h; slow: ≥2.2 h). Expected exposure was defined by a Cmax of 3-6 mg/L, while target exposure was defined by an AUC₀₋₂₄ₕ above 10.5 h·mg/L for bactericidal efficacy and below 21.8 h·mg/L to minimize the risk of hepatotoxicity. RESULTS: Among 109 patients (66.1% male, median age 40.7 years, 69.8% pulmonary tuberculosis), AUC₀₋₂₄ₕ showed high interindividual variability (range 3.4-62.8 h·mg/L, coefficient of variation 59.4%), independent of weight-adjusted dosing (Pearson's r=-0.016, p=0.875). Slow acetylators predominated (59%). With a median dose of 4.1 mg/kg, 24 patients (22%) had subtherapeutic AUC₀₋₂₄ₕ (<10.5 h·mg/L), while 52 (47.7%) exceeded the hepatotoxicity risk threshold (>21.8 h·mg/L). Nearly one-third had Cmax within the expected range but AUC₀₋₂₄ₕ above the safety limit. CONCLUSION: Real-world data reveal substantial isoniazid exposure variability, with frequent deviations from target AUC₀₋₂₄ₕ. These findings advocate for systematic TDM and individualized dosing, prioritizing AUC₀₋₂₄ₕ as a key monitoring parameter.