Abstract
BACKGROUND: Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS: A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R(2) randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R(20)) and 30 mg/kg/day (2R(30)), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R(10)) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC(0-24)) and peak concentration (C(max)) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC(0-24) and C(max). RESULTS: We enrolled 51 participants in this study. In the 4R(10), 2R(20,) and 2R(30) arms, the geometric mean AUC(0-24) was 68.0, 186.8, and 289.9 h⋅mg/L, and C(max) was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R(10) arm, AUC(0-24) and C(max) were significantly higher in the 2R(20) and 2R(30) arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC(0-24) and C(max) (P < 0.05). AUC(0-24) and C(max) values were much higher than those previously reported in persons with TB disease. CONCLUSIONS: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.
