Population Pharmacokinetic Modeling of Standard- and High-Dose Rifampicin for Tuberculosis Preventive Therapy in the 2R2 Randomized Controlled Trial

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Abstract
Background: 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. Methods: Intensive and sparse pharmacokinetic substudies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared 2 months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with 4 months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥ 10 years. Venous blood samples were collected after 4 weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling in NONMEM. Results: Among 1368 trial participants, 440 were included in model development (51 intensive and 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A 1-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. All 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% confidence interval [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. Conclusions: High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to nonlinear 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.
Funding Information
  • Canadian Institutes of Health Research (FDN-143350)
  • Fonds de recherche du Québec

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