Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

Abstract

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 μg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 μg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 μg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

FIG 1

Mean plasma rifampin (RMP) concentrations (μg/ml) after the intake of a mean dose of 12.9 mg/kg for RMP formulation 1 (n = 14) and of a mean dose of 16.7 mg/kg for RMP formulation 2 (n = 25). C_max adult target values, 8 to 24 μg/ml when RMP is administered at 600 mg daily in American adults (23); C_max, 5.9 μg/ml when RMP is administered at 10.9 mg/kg in South African adults (24).

FIG 2

Mean plasma isoniazid (INH) concentrations (μg/ml) after the intake of a mean dose of 12.8 mg/kg of INH (n = 39). Adult target C_max values, 3 to 6 μg/ml when INH is administered at 300 mg daily in American adults (23); C_max, 6.5 μg/ml when INH is administered at 6.5 mg/kg in South African adults (24).

FIG 3

Mean plasma pyrazinamide (PZA) concentrations (μg/ml) after the intake of a mean dose of 33.3 mg/kg of PZA (n = 39). Adult target C_max values, 20 to 50 μg/ml when PZA is administered at 25 mg/kg/day in American adults (23); C_max, 52.7 μg/ml when INH is administered at 35.7 mg/kg in South African adults (24).

FIG 4

Mean plasma ethambutol (EMB) concentrations (μg/ml) after the intake of a mean dose of 20.2 mg/kg of EMB (n = 16). Adult target C_max values, 2 to 6 μg/ml administered at 25 mg/kg/day in American adults (23); C_max, 5 μg/ml when EMB is administered at 24.5 mg/kg in South African adults (24).