Journal
CLINICAL INFECTIOUS DISEASES
Volume 75, Issue 1, Pages 141-151Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cid/ciab908
Keywords
children; first-line tuberculosis treatment; fixed-dose combination; NONMEM; pharmacokinetics
Categories
Funding
- National Institutes of Health (NIH [Bethesda, Maryland, USA])
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD069175]
- Wellcome Trust [206379/Z/17/Z]
- PanACEA, European and Developing Countries Clinical Trials Partnership (EDCTP) 2 programme - European Union [TRIA2015-1102-PanACEA]
- SA-MRC
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health [UM1 AI068634, UM1 AI068636, UM1 AI106701]
- Wellcome Trust [206379/Z/17/Z] Funding Source: Wellcome Trust
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The dosing guidelines for childhood tuberculosis need to be revised as current pediatric FDC doses result in low rifampicin exposures. New fixed-dose combination (FDC) with revised weight bands could improve treatment for children with drug-susceptible tuberculosis.
Background In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC(0-24h) for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg center dot h/L). Results In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. Conclusions Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands. Current pediatric dosing guidelines lead to infant rifampicin exposures much lower than in adults, whereas isoniazid and pyrazinamide exposures are similar. A new fixed-dose combination (FDC) with rifampicin/isoniazid/pyrazinamide 120/35/130 mg and weight bands of < 6, 6-13, 13-20, and 20-25 kg could improve treatment.
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