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

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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/m2 and baseline serum albumin < 4 g/dl predicted risk of DIH on univariate analyses. Free and total plasma RMP levels (Cmax and AUC0–4) on days 1, 7 and 14 were significantly higher in cases compared to controls and predicted development of DIH. Day 7 total RMP Cmax and AUC0–4 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 Cmax of Day 7 total RMP level (cut-off 12.50 mg/l) predicted subsequent development of DIH in 93.3% of the patients.

Keywords: anti-tuberculosis drugs; drug induced hepatotoxicity; plasma drug levels; rifampicin

Document Type: Research Article

Affiliations: 1: Department of Medicine, All India Institute of Medical Sciences, New Delhi, India 2: Department of Ocular Pharmacology and Pharmacy, Dr Rajender Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India 3: Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India 4: Medical University, Pleven, Bulgaria 5: Department of Ophthalmology, Dr Rajender Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India 6: Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India 7: Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India

Publication date: February 1, 2014

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