Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations

Abstract

Background: Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial.

Methods: Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment.

Results: In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, and ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults.

Conclusions: Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.

Keywords: antituberculosis drugs; children; dosing; pharmacokinetics; tuberculosis.

Figure 1.

Box plots for the area under the concentration-time curve from 0 to 24 hours (AUC₂₄) for rifampicin, isoniazid, pyrazinamide, and ethambutol in children treated for tuberculosis, by weight band. Horizontal reference lines represent target exposures derived from adult studies. For rifampicin, the estimated AUC₂₄ (38.73 mg⋅h/L) was derived from a systematic review and meta-analysis by Stott et al [22]. For isoniazid, pyrazinamide, and ethambutol, 11.6–26.3, 233–429, and 16–28 mg/L represent the respective ranges of the medians from studies in a systematic review by Daskapan et al [23].

Figure 2.

Box plots for rifampicin, isoniazid, pyrazinamide, and ethambutol peak concentration (C_max) in children treated for tuberculosis, by weight band. Horizontal reference lines represent the target reference ranges for C_max recommended by Alsultan and Peloquin [16]: 3–6 mg/L, 8–24 mg/L, 20–60 mg/L, and 2–6 mg/L for isoniazid, rifampin, pyrazinamide, and ethambutol, respectively.