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

by Lufina Tsirizani Galileya, Roeland E. Wasmann, Chishala Chabala, Helena Rabie, Janice Lee, Irene Njahira Mukui, Anneke Hesseling, Heather Zar, Rob Aarnoutse, Anna Turkova, Diana Gibb, Mark F. Cotton, Helen McIlleron, Paolo Denti BackgroundThe 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 findingsWe 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 int...
Source: PLoS Medicine - Category: Internal Medicine Authors: Source Type: research