Pharmacokinetics of standard versus high-dose rifampin for tuberculosis preventive treatment: a sub-study of the 2R2 randomized controlled trial

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 two months of high-dose rifampin at 20 mg/kg/day (2R 20) and 30 mg/kg/day (2R 30), with four 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 inter-individual 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 reported in persons with TB disease.

CONCLUSION: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modeling and simulations are warranted to support shortening of TPT regimens with high-dose rifampin.