Abstract
BackgroundDispersible 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.MethodsChildren 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.ResultsIn 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.ConclusionsRecommended 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.
Highlights
Tuberculosis treatment regimens in most low-and-middle income countries is standard based on World Health Organization (WHO) recommendations and delivered by national programmes in the public sector
Other important factors include the type of formulation, ipt dose preparation and administration, drug-drug interactions, and laboratory assay methods used r [20, 21]. c The revised WHO weight-band dosing, using dispersible child-friendly fixed dose ted combination (FDC), simplifies TB treatment us and programmatic implementation but supporting pharmacokinetic evidence in children is lacking. n We describe the pharmacokinetics at steady-state in children dosed with this approach in the SHINE Accepted Ma trial and sought to identify predictors of exposures of first-line antituberculosis drugs
Ethambutol was us measured in 22 children who received it as part of their regimen. n The median AUC24 (IQR) for rifampicin was 32.5 (20.1 - 45.1) mg.h/L
Summary
Tuberculosis treatment regimens in most low-and-middle income countries is standard based on World Health Organization (WHO) recommendations and delivered by national programmes in the public sector. Informed by ip pharmacokinetic studies demonstrating that this approach does not achieve comparable drug r exposures in children[2,3,4,5], the WHO revised these recommendations for children weighing less than c 25kg in 2010, increasing the daily doses of isoniazid (H) by 100% to 10 (range 7-15) mg/kg, us rifampicin (R) by 50% to 15 (range 10-20) mg/kg, and pyrazinamide (Z) to 35 (range 30-40) mg/kg. Dispersible paediatric fixed dose combination (FDCs) tablets delivering higher doses of first-line antituberculosis drugs in WHO-recommended weight-bands were introduced in 2015. Children 25.0-36.9 kg received doses recommended r for adults
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