Assessment of four first-line anti-tuberculosis drug exposure in pulmonary tuberculosis patients with drug-induced hepatotoxicity

Aims: Literature data suggest that up to 30% of patients with tuberculosis (TB) experience drug-induced hepatotoxicity (DIH), which may require treatment discontinuation. Various DIH risk factors have been proposed, albeit information on the role of drug exposure in DIH occurrence is limited. Therefore, this study aimed to investigate the exposure of four first-line anti-TB drugs (pyrazinamide [PZA], rifampicin [RIF], isoniazid [IZN], ethambutol [ETB]) among TB patients with DIH.

Methods: The study population comprised patients with pulmonary TB (n = 46) admitted to the Riga East University Hospital, Centre of Tuberculosis and Lung Diseases. The DIH was determined based on blood biochemical findings before and 10 days after anti-TB treatment onset. The anti-TB drug concentration in blood plasma was measured using LC-MS/MS method in samples collected pre-dose, 2 h and 6 h post-dose.

Results: Six TB patients (13.0%) developed mild to severe DIH characterized by ALAT/ASAT >1.5 times upper limit of normal with/without changes in total and conjugated bilirubin levels (>19.0 and >3.4 μmol/L, respectively). Overall, plasma concentration 2 h post-dose corresponded target therapeutic range for all drugs except RIF (Mdn = 2.1 μg/mL vs. recommended 8.0 μg/mL). Further analysis revealed that patients with DIH had significantly higher PZA AUC0-6h (U = 194, p = 0.014). Additionally, subgroup analysis showed that conjugated hyperbilirubinemia observed in 12 patients (26.1%) was associated with higher PZA, RIF, IZN AUC0-6h (U = 338, p = 0.001; U = 328, p = 0.002; U = 301; p = 0.015) independently of other biochemical markers.

Conclusion: The DIH incidence in patients with TB was consistent with findings reported globally. Although anti-TB drug concentrations detected 2 h post-dose did not indicate overexposure to any drug, the PZA appears to trigger exposure-dependent hepatotoxicity even within the therapeutic range. The conjugated hyperbilirubinemia may reflect a clinically insignificant physiological response to anti-TB treatment.