Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization–Recommended Weight Band Doses and Formulations. (22nd August 2021)

• Record Type: Journal Article
• Authors: Chabala, Chishala; Turkova, Anna; Hesseling, Anneke C; Zimba, Kevin M; van der Zalm, Marieke; Kapasa, Monica; Palmer, Megan; Chirehwa, Maxwell; Wiesner, Lubbe; Wobudeya, Eric; Kinikar, Aarti; Mave, Vidya; Hissar, Syed; Choo, Louise; LeBeau, Kristen; Mulenga, Veronica; Aarnoutse, Robb; Gibb, Diana; McIlleron, Helen
• Is Part Of: Clinical infectious diseases. Volume 74:Number 10(2022)
• Page Start: 1767
• Page End: 1775
• Publication Date: 2021-08-22
• Subjects: antituberculosis drugs -- children -- dosing -- pharmacokinetics -- tuberculosis; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciab725
• Languages: English
• ISSNs: 1058-4838

Abstract

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. Abstract : We evaluated pharmacokinetics of antituberculosis drugs administered as fixed-dose combinations tablets using WHO weight band (WB) dosing tables. Exposures were low for rifampicin and isoniazid in WBs 4.0 <8kg and ≥25kg; 8kg-12kg for rifampicin; and across all WBs for ethambutol.