Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis

Abstract

Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · μg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 μg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.).

Keywords: antitubercular agents; pharmacokinetics; rifampin; tuberculosis.

Copyright © 2017 American Society for Microbiology.

Figures

FIG 1

Box-and-whisker plot of the rifampin AUC0–6 (h · μg/ml) versus the randomized dose (mg/kg). The lower and upper hinges correspond to the 25th and 75th percentiles, and the middle line corresponds to the median. The whiskers extend from the hinge to the smallest or largest value no further than 1.5 times the IQR from the hinge.

FIG 2

Box-and-whisker plot of the rifampin Cmax (μg/ml) versus the randomized dose (mg/kg). The lower and upper hinges correspond to the 25th and 75th percentiles, and the middle line corresponds to the median. The whiskers extend from the hinge to the smallest or largest value no further than 1.5 times the IQR from the hinge.