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Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis
Lufina Tsirizani Galileya1,2, Roeland E Wasmann1, Chishala Chabala1,3,4
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Plos Medicine
|November 21, 2023
Summary
Pediatric tuberculosis drug dosing needs optimization. Increasing rifampicin doses for children over 3 months can improve exposure and therapy, while HIV drug interactions require further study.
Area of Science:
- Pharmacokinetics and pharmacodynamics
- Pediatric infectious diseases
- Tuberculosis treatment
Background:
- Current World Health Organization (WHO) pediatric tuberculosis dosing guidelines result in suboptimal drug exposures.
- Pediatric pharmacokinetic studies are often small, leading to variability and uncertainty in results.
- Pooling data from large pharmacokinetic studies is essential for optimizing pediatric tuberculosis dosing.
Purpose of the Study:
- To identify key covariates influencing drug exposure in children undergoing tuberculosis treatment.
- To optimize tuberculosis dosing regimens for pediatric populations.
- To characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in children.
Main Methods:
- Utilized nonlinear mixed-effects modeling to analyze pharmacokinetic data from 387 children across four countries.
- Investigated the impact of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size on drug pharmacokinetics.
- Employed allometry to scale clearance and volume of distribution for rifampicin, isoniazid, and pyrazinamide.
Main Results:
- Age significantly affected the bioavailability and clearance of rifampicin and isoniazid, with children reaching adult levels after 2 years and full clearance maturation around 3 years.
- HIV infection itself did not alter pharmacokinetics, but antiretroviral therapy (ART) showed significant interactions: lopinavir/ritonavir decreased rifampicin clearance and increased pyrazinamide clearance, while efavirenz and lopinavir/ritonavir reduced isoniazid bioavailability.
- Simulations indicated that current WHO-recommended doses lead to lower rifampicin exposures in children over 3 months, suggesting a need for dose adjustment.
Conclusions:
- Children over 3 months exhibit lower rifampicin exposures than adults, necessitating dose increases of 75-150 mg to improve therapy.
- Altered drug exposures in children with HIV are likely due to concomitant ART, not HIV infection itself.
- Further evaluation of drug-drug interactions between tuberculosis medications and ART (lopinavir/ritonavir, efavirenz) is crucial for future dosing guidance.
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