Evaluating pediatric tuberculosis dosing guidelines : A model-based individual data pooled analysis

Copyright: © 2023 Galileya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited..

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.

METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.

CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.

TRIAL REGISTRATION: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Medienart:	E-Artikel

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	Zur Gesamtaufnahme - volume:20
Enthalten in:	PLoS medicine - 20(2023), 11 vom: 18. Nov., Seite e1004303

Sprache:	Englisch

Beteiligte Personen:

Galileya, Lufina Tsirizani [VerfasserIn] Wasmann, Roeland E [VerfasserIn] Chabala, Chishala [VerfasserIn] Rabie, Helena [VerfasserIn] Lee, Janice [VerfasserIn] Njahira Mukui, Irene [VerfasserIn] Hesseling, Anneke [VerfasserIn] Zar, Heather [VerfasserIn] Aarnoutse, Rob [VerfasserIn] Turkova, Anna [VerfasserIn] Gibb, Diana [VerfasserIn] Cotton, Mark F [VerfasserIn] McIlleron, Helen [VerfasserIn] Denti, Paolo [VerfasserIn]

Links:	Volltext

Themen:	2494G1JF75 2KNI5N06TI Antitubercular Agents Efavirenz Isoniazid JE6H2O27P8 Journal Article Lopinavir O3J8G9O825 Pyrazinamide Rifampin Ritonavir V83O1VOZ8L VJT6J7R4TR

Anmerkungen:	Date Completed 23.11.2023 Date Revised 13.03.2024 published: Electronic-eCollection ClinicalTrials.gov: NCT02348177, NCT01637558 Citation Status MEDLINE

doi:	10.1371/journal.pmed.1004303

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	NLM36479769X