Abstrak 
Pharmacokinetics And Tolerability Of A Higher Rifampin Dose Versus The Standard Dose In Pulmonary Tuberculosis Patients
Rovina Ruslami, Bachti Alisjahbana, and Ida Parwati
Unpad
Inggris
Unpad
pharmacokinetics, Rifampin, The treatment of TB
Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to investigate the effect of a higher dose of rifampin in terms of pharmacokinetics and tolerability. Fifty newly diagnosed adult Indonesian TB patients were randomized to receive a standard (450-mg, i.e., 10-mg/kg in Indonesian patients) or higher (600-mg) dose of rifampin in addition to other TB drugs. A full pharmacokinetic curve for rifampin, pyrazinamide, and ethambutol was recorded after 6 weeks of daily TB treatment. Tolerability was assessed during the 6-month treatment period. The geometric means of exposure to rifampin (area under the concentration- time curve from 0 to 24 h [AUC0–24]) were increased by 65% (P < 0.001) in the higher-dose group (79.7 mg h/liter) compared to the standard-dose group (48.5 mg h/liter). Maximum rifampin concentrations (Cmax) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin Cmax was >8 mg/liter was 96% versus 79% (P 0.094). The pharmacokinetics of pyrazinamide and ethambutol were similar in both groups. Mild (grade 1 or 2) hepatotoxicity was more common in the higher-dose group (46 versus 20%; P 0.054), but no patient developed severe hepatotoxicity. Increasing the rifampin dose was associated with a more than dose-proportional increase in the mean AUC0–24 and Cmax of rifampin without affecting the incidence of serious adverse effects. Follow-up studies are warranted to assess whether high-dose rifampin may enable shortening of TB treatment.