Might isoniazid plasma exposure be a valuable predictor of drug-related hepatotoxicity risk among adult patients with TB?

To investigate the relationship between isoniazid plasma exposure and the likelihood of elevation of ALT (a parts per thousand yen51 IU/L) among adult patients with TB. A retrospective observational study was conducted in patients who underwent periodic monitoring of hepatic function and in whom pharmacokinetic data were collected. Monte Carlo simulation was performed with the intent of identifying the probability of achieving an AUC(24) greater than the identified threshold of hepatotoxicity with different dosing regimens (2.5, 5.0 and 7.5 mg/kg/day). Forty-one out of 185 evaluable patients (22.2%) had an ALT elevation. A mild correlation between isoniazid AUC(0-24) and ALT increase was observed (Spearman's rho aEuroS=aEuroS0.34, PaEuroS < aEuroS0.001). Patients with ALT a parts per thousand yen51 IU/L showed significantly higher isoniazid exposure than those with ALT < 51 IU/L (mean AUC(24) of 58.33 versus 31.28 mg center dot h/L, PaEuroS < aEuroS0.001). The probabilities of ALT elevation were 0.82 and 0.12 for isoniazid AUC(24) a parts per thousand yen55.0 and < 55.0 mg center dot h/L, respectively. Use of a logistic regression model estimated a likelihood of developing hepatotoxicity of 0.5 and 0.9 when in the presence of an isoniazid AUC(24) of 53.7 and 70.0 mg center dot h/L, respectively. Simulation showed that the standard isoniazid 5 mg/kg daily dose gave a probability of ALT increase of 0.46 for slow acetylators and 0.03 for rapid acetylators. Plasma isoniazid exposure might be a valuable predictor of drug-related hepatotoxicity. Early assessment of isoniazid exposure at the beginning of treatment might allow prompt dosage reduction among those patients who are experiencing drug overexposure, thus containing the risk of hepatotoxicity occurrence.