Bekker, Adrie

Davies, Gerry

Denti, Paolo

Gonzalez-Martinez, Carmen

Hesseling, Anneke C.

McIlleron, Helen M.

Rabie, Helena

Svensson, Elin M.

van der Laan, Louvina E.

Van Rie, Annelies

Wasmann, Roeland E.

Wiesner, Lubbe

Winckler, Jana

Zar, Heather J.

Abstract: 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 19h/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-band

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Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis : a prospective population pharmacokinetic study

Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis : a prospective population pharmacokinetic study

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Institutional Repository Universiteit Antwerpen