Population pharmacokinetic modeling of standard- and high-dose rifampicin for tuberculosis preventive therapy in the 2R2 randomized controlled trial.

Abstract

High-dose rifampicin could potentially shorten tuberculosis preventive therapy (TPT) and improve outcomes. We aimed to characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT among individuals with tuberculosis infection. Intensive and sparse pharmacokinetic sub-studies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared two months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with four months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥10 years. Venous blood samples were collected after four weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling. Among 1368 trial participants, 440 were included in model development (51 intensive, 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A one-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. Disposition parameters were allometrically scaled using fat-free mass. Country-specific differences, particularly variation in drug formulation, were associated with lower bioavailability in Canada (-21.8% [95%CI -27.9 to -18.0%]) and Vietnam (-12.3% [95%CI -17.7 to -7.9%]) compared with Indonesia. The 24-hour area under the concentration-time curve increased more than proportionally with dose and was higher across treatment arms in Indonesia, followed by Vietnam and Canada. High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to non-linear clearance at higher doses. Substantial between-country variability in exposure was observed, which may have been due to multiple factors, including differences in country-specific formulations, fat-free mass, and unmeasured confounders.