Adequacy of WHO weight-band dosing and fixed-dose combinations for the treatment of TB in children

Abstract

BACKGROUND: We examined whether the updated WHO weight-band dosing recommendations and fixed-dose combination tablets for the treatment of TB in children achieves recommended calculated dosages and adequate drug plasma exposure.DESIGN/METHODS: Children on first-line TB treatment per WHO guidelines were enrolled. Blood sampling at pre-dose, 1, 2, 4, 8, and 12 h post-dose after at least 4 weeks of treatment was performed. Drugs concentrations were measured using validated liquid chromatography tandem with mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Plasma drug exposure below the lower limit of the 95% confidence interval of the mean for children was considered low and above the upper limit was high.RESULTS: Of 71 participants, 34 (47.9%) had HIV coinfection. The median calculated dose for isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) was 10.0 (range 4.3-13.3), 15.0 (range 8.6-20.0), 30.0 (range 21.0-40.0), and 20.4 (range 14.3-26.7) mg/kg, respectively. Overall, most patients had under-exposure for RIF and PZA and over-exposure for INH and EMB. Drug dose and weight-for-age Z-score were associated with area under the curve from time 0-24 h for all drugs.CONCLUSIONS: Despite adherence to WHO dosing guidelines, low PZA and RIF plasma exposures were frequent in our study population. Higher than currently recommended dosages of RIF and PZA may be needed in children.

Figure 1.

Boxplots for rifampin, isoniazid, pyrazinamide and ethambutol AUC_0–24h in children treated for tuberculosis and by weight-band. Bars represent geometric mean; horizontal dash line represent 95% confidence interval of global pediatric estimates normalized for WHO recommended dose (isoniazid 15.5 – 22.6, rifampin 29.4 – 40.3, pyrazinamide 339.9 – 413.7, and ethambutol 6.4 – 10.0 mg*h//L).