Population Pharmacokinetic Modeling of Standard- and High-Dose Rifampicin for Tuberculosis Preventive Therapy in the...

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Infectious Diseases
• Drug Development

Background:

• High-dose rifampicin shows potential to shorten tuberculosis preventive therapy (TPT).
• Understanding rifampicin pharmacokinetics is crucial for optimizing TPT regimens.
• This study characterizes population pharmacokinetics of standard- and high-dose rifampicin in individuals with tuberculosis infection.

Purpose of the Study:

• To characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT.
• To evaluate the impact of different dosing regimens on rifampicin exposure.
• To identify factors contributing to variability in rifampicin pharmacokinetics.

Main Methods:

• A randomized trial (2R2) compared two months of high-dose rifampicin (20 or 30 mg/kg/day) with four months of standard-dose rifampicin (10 mg/kg/day).
• Pharmacokinetic sub-studies were conducted in Indonesia, Canada, and Vietnam.
• Nonlinear mixed-effects modeling was used to analyze rifampicin pharmacokinetics from intensive and sparse sampling.

Main Results:

• A one-compartment model with transit-compartment absorption and saturable hepatic extraction best described rifampicin pharmacokinetics.
• Lower bioavailability was observed in Canada (-21.8%) and Vietnam (-12.3%) compared to Indonesia, potentially due to drug formulation differences.
• The 24-hour area under the concentration-time curve increased more than proportionally with dose, with higher exposure in Indonesia, followed by Vietnam and Canada.

Conclusions:

• High-dose rifampicin leads to greater-than-proportional increases in exposure due to non-linear clearance at higher doses.
• Substantial between-country variability in rifampicin exposure was observed.
• Factors such as country-specific formulations, fat-free mass, and unmeasured confounders likely contribute to observed pharmacokinetic variability.