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Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis

Journal Contribution - Journal Article

Subtitle:a prospective population pharmacokinetic study
Background: In 2010, the 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) table 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 modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results: 180 children (42% female; 13.9% HIV-infected; 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 three drugs. Conclusion: 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
Journal: Clinical infectious diseases
ISSN: 1058-4838
Volume: 75
Pages: 141 - 151
Publication year:2022
Keywords:A1 Journal article