Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients

Abstract

Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

FIG. 1.

Median concentration of rifampin at each sampling time for participants who received approved products (n = 88). Error bars indicate the ranges of concentrations at each sampling time, and the boxes represent the 25% to 75% percentile ranges.

FIG. 2.

Median concentrations of isoniazid at each sampling time (n = 142). Error bars indicate the ranges of concentrations at each sampling time, and the boxes represent the 25% to 75% percentile ranges.

FIG. 3.

Median concentrations of pyrazinamide at each sampling time (n = 142). Error bars indicate the ranges of concentrations at each sampling time, and the boxes represent the 25% to 75% percentile ranges.

FIG. 4.

Median concentrations of ethambutol at each sampling time (n = 129). Error bars indicate the ranges of concentrations at each sampling time, and the boxes represent the 25% to 75% percentile ranges.