Pharmacokinetics of isoniazid in Indian children with tuberculosis on daily treatment.

OBJECTIVE: To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. METHODS: INH levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1-15 years on daily anti-tuberculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after INH administration. The maximum concentration (Cmax) and area under the curve (AUC0-24) were determined. The normal therapeutic range for Cmax is 3-5 µg/ml. An AUC of <10.52 µg•h/ml for INH is low. RESULTS: The mean Cmax was 8.3 ± 4.28 µg/ml and was attained in 1.22 ± 0.5 h, with a median time to Cmax (Tmax) of 1 h. The mean AUC for INH was 46.23 ± 34.82 µg•h/ml. Children aged 1-4.9 years, 5-10 years and >10 years had a mean Cmax of respectively 9.87 ± 5.75 µg/ml, 7.62 ± 3.37 µg/ml and 7.21 ± 2.50 µg/ml (P = 0.08) and a mean AUC of respectively 60.97 ± 49.90 µg•h/ml, 38.95 ± 22.28 µg•h/ml and 36.09 ± 13.56 µg•h/ml (P = 0.29). The mean Cmax in children taking fixed-drug combinations and individual drugs was respectively 9.07 ± 4.67 µg/ml and 7.43 ± 3.71 µg/ml (P = 0.26); the mean AUC was respectively 50.48 ± 38.38 µg•h/ml and 41.20 ± 30.52 µg•h/ml (P = 0.44). Two children had hepatitis. CONCLUSION: Most Indian children had higher than normal INH AUC and Cmax values. It is necessary to determine the ideal dose of INH in Indian children using the genotypic acetylator status of the patients and pharmacokinetic toxicity analysis.