Denti, Paolo, Wasmann, Roeland E, van Rie, Annelies, Winckler, Jana, Bekker, Adrie, Rabie, Helena, Hesseling, Anneke C, van der Laan, Louvina E, Gonzalez-Martinez, Carmen, Zar, Heather J et al (show 4 more authors)
(2021)
Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.
CLINICAL INFECTIOUS DISEASES, 75 (1).
pp. 141-151.
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Denti et al. - 2021 - Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients wit.pdf - Author Accepted Manuscript Download (2MB) | Preview |
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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 AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L).<h4>Results</h4>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.<h4>Conclusions</h4>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | children, first-line tuberculosis treatment, fixed-dose combination, NONMEM, pharmacokinetics |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 04 Oct 2022 07:44 |
| Last Modified: | 18 Jan 2023 20:41 |
| DOI: | 10.1093/cid/ciab908 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165025 |
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