Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity

OBJECTIVES: To compare the free and total plasma drug concentrations of rifampicin (RMP), isoniazid and pyrazinamide in subjects with or without anti-tuberculosis drug-induced hepatotoxicity (DIH). METHODS: A total of 110 tuberculosis (TB) patients were administered daily anti-tuberculosis treatment and were prospectively followed for the development of DIH. Plasma drug levels were measured at 0, 1, 2 and 4 h on days 1, 7 and 14 of treatment. Plasma drug levels in 15 patients who developed DIH (cases) were compared with 95 patients who did not (controls). RESULTS: Female sex, body mass index < 17 kg/m(2) and baseline serum albumin <4 g/dl predicted risk of DIH on univariate analyses. Free and total plasma RMP levels (C-max and AUC(0-4)) on days 1, 7 and 14 were significantly higher in cases compared to controls and predicted development of DIH. Day 7 total RMP C-max and AUC(0-4) were higher in cases (mean 26.73, standard deviation [SD] 5.72 and 47.58, SD 33.10) than in controls (7.87, SD 10.95 and 14.01, SD 10.69, respectively). CONCLUSIONS: Plasma RMP levels were higher in cases than in controls and independently predicted subsequent development of DIH. The C-max of Day 7 total RMP level (cut-off 12.50 mg/l) predicted subsequent development of DIH in 93.3% of the patients.