Yuanxi Zou: Applications of pharmacometrics to improve treatment of multi-drug resistant tuberculosis in children

Abstract

Tuberculosis (TB) remains a significant global health threat as one of the leading causes of death from an infectious agent. Despite decades of global efforts, an estimated 25000-32000 children develop multidrug-resistant (MDR) TB each year, yet only about 3000 children are diagnosed and treated. Critical gaps remain in paediatric TB research to generate evidence for dosing optimisation, ensuring timely access for children to effective and safe treatment. The overall aim of this thesis was to use pharmacometric tools to support paediatric clinical study design and establish robust evidence bases for paediatric dosing with paediatric-friendly options in MDR-TB treatment.  

A population pharmacokinetic model was developed for pretomanid with its newly developed child-friendly dispersible tablet formulation based on healthy adult data. The absorption properties of this new formulation were compared with the marketed formulations to assess its dosing implications in children or patients with swallowing difficulty. For delamanid, the bioavailability of the crushed and dispersed adult tablets was compared with the reference whole tablets in healthy adults through population pharmacokinetic modelling. This was to evaluate the feasibility of crushing delamanid adult tablets for use in children before the paediatric formulations become widely available. 

The population pharmacokinetics of new child-friendly formulations of moxifloxacin and clofazimine were characterised in children with TB from a multisite trial. Both drugs demonstrated absorption properties comparable to routinely used adult formulations. For moxifloxacin, the currently available dosing table was evaluated and optimised dosing was proposed based on the developed model. 

An approach was proposed for evaluating paediatric pharmacokinetic study design, focusing on a directly clinically relevant criterion, accuracy of dose selection, as an alternative to parameter precision, a commonly used criterion. The new approach evaluated the ability of a given design to accurately select doses that achieved closest-to-target exposures. This approach could support paediatric clinical trial development by balancing the study objectives and efficiency, potentially reducing costs and recruitment challenges. 

In summary, this thesis has, through pharmacometric applications, provided evidence to support the improvement of MDR-TB treatment in children, including the pharmacokinetics of child-friendly formulations for priority anti-TB drugs, optimized paediatric dosing, and paediatric pharmacokinetic clinical trial designs.