Editor’s Note: Children are the future of humanity and an essential resource for sustainable social development. However, approximately 1.2 million children and adolescents worldwide are threatened by tuberculosis (TB), with drug-resistant TB complicating treatment. To optimize pediatric TB drug treatment strategies, the World Health Organization (WHO) held the second Pediatric Drug Optimization for Tuberculosis (PADO-TB) meeting from October 3-5, 2023. This issue of "Shenzhen Third People's Hospital Tuberculosis Window" summarizes the key points from this conference report.

Meeting Background

In 2022, it was estimated that out of 10.6 million TB patients, 1.25 million (12%) were children and adolescents, with 47% of these children under five years old. Additionally, in 2022, 3,900 children were diagnosed and treated for multidrug-resistant and rifampicin-resistant TB (MDR/RR-TB), far below the estimated 25,000 – 32,000 children and adolescents with MDR/RR-TB.

Optimizing pediatric TB drugs is a crucial action and milestone in the “Roadmap towards Ending TB in Children and Adolescents (Third Edition),” helping to achieve the specific goals set at the second UN High-Level Meeting on TB in 2023 to end TB among children and adolescents.

Considering WHO’s latest recommendations on drug-susceptible TB (DS-TB), drug-resistant TB (DR-TB), and TB preventive treatment (TPT), the progress of new TB drugs and formulations since February 2019, clinical trial results, pharmacokinetic (PK) and pharmacodynamic (PD) studies, and key drugs in TB research and development, WHO held the second PADO-TB meeting (PADO-TB2) from October 3-5, 2023.

Meeting Objectives

1-Review existing TB drug formulations based on current WHO recommendations, completed and ongoing research evidence, and assess their suitability for different pediatric age groups.

2-Review TB drugs being studied in Phase IIa and III clinical trials (adults) and evaluate which of these should be prioritized for pediatric development in the future.

3-Identify key research gaps in preventing and treating pediatric DS-TB and MDR/RR-TB to ensure children with various forms of TB have rapid access to the best available treatment regimens.

Meeting Content

1-Acceptability of Pediatric TB Drug Treatment Beyond Palatability TB drug acceptability encompasses three aspects: palatability (taste and smell), manageability (how well the treatment integrates into daily life and adherence over time), and appeal (size, color of the dosage form, packaging, and accompanying instructions). Patient acceptance involves their perceptions and expectations of the treatment and its practical use. Comprehensive factors include socio-economic environment and healthcare system delivery models (e.g., level of care provided, accessibility, and availability of TB treatment-related services), affecting the ease of receiving TB treatment.

2-TB Preventive Treatment and Rifapentine Rifapentine is a key component of WHO-recommended regimens for TB prevention and DS-TB treatment. During PADO-TB2, ongoing and completed studies involving rifapentine were reviewed. Features of New Pediatric-Friendly Rifapentine Formulations: Allows 75 mg dosage increments. Rapid dispersion in about 10 ml of water. Raspberry or mint-flavored taste. Recommended packaging: Alu/Alu strips or similar. Storage: Below 30°C, avoiding excessive heat and moisture. Shelf life: 18 months (stability testing extending to 24 months). Due to the raspberry/mint flavor of rifapentine dispersible tablets and the strawberry flavor of isoniazid dispersible tablets, palatability is not expected to be an issue.

3-First-Line TB Drugs Studies have shown that effective drug concentrations of rifampicin, pyrazinamide, and ethambutol are typically lower in children than in adults, posing adverse risk outcomes. Observations indicated that effective drug concentrations of all first-line TB drugs were lower, especially in children under two years old, due to the non-linear effect of weight on clearance, leading to lower effective concentrations compared to older children and adolescents. This might also be due to lower bioavailability of some formulations (isoniazid and rifampicin) in children under 2-3 years old. Emerging evidence suggests that current fixed-dose combinations (FDCs) do not achieve optimal dosages of first-line TB drugs, particularly in young children. The Opti-Rif study indicated that children require daily doses of 65-70 mg/kg of rifampicin to reach effective drug concentrations comparable to adults receiving 35 mg/kg daily.

4-Second-Line TB Drugs All 11 WHO-recommended drugs for MDR-TB are now available in pediatric-friendly formulations. The PADO-TB2 summarized the existing dosage forms, strengths, number of suppliers, and the suitability of current formulations. All formulations are suitable for achieving target effective concentrations across the pediatric age range, though some formulations’ palatability needs improvement.

5-Ongoing Drug Development and New Technologies Long-acting formulations of rifapentine and isoniazid are being researched for delivery via microarray patches, allowing weekly dosing for children. Microarray patches are particularly attractive for the pediatric population, offering controlled drug release incompatible with other long-acting methods. The application time for the patches is short (hours), and the microneedles (comprising the long-acting formulation) biodegrade, releasing the drug in the dermis, thus eliminating the need for needle removal. In the short term, the complexity of manufacturing and unfamiliarity with the technology may pose challenges to production and implementation.