Cheng, Iek Leng; (2025) Population pharmacokinetic modelling for personalised medicine in paediatric immunodeficiencies and haematopoietic stem cell transplant patients : a focus on immunoglobulin, ciclosporin, and favipiravir. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Children experience rapid developmental changes in how they absorb, distribute, metabolise, and eliminate medicines. These maturational effects are particularly critical in immunocompromised patients, where precise dosing can be pivotal in maximising therapeutic benefit while minimising the risk of serious harm. Children with primary immunodeficiencies may require haematopoietic stem cell transplantation (HSCT) for a definitive cure, a high-risk procedure that requires carefully coordinated use of supportive medicines such as immunosupressants and antimicrobials. This thesis addresses the evidence gap in this population by using pharmacokinetic (PK) modelling to study three key therapies in immunocompromised children, ciclosporin, immunoglobulin, and favipiravir, using real-world data from patients aged 0–18 years. In HSCT, effective immunosuppression is essential to protect the donor graft while avoiding toxicity. Ciclosporin, a key agent in this setting, has a narrow therapeutic range, overexposure can lead to serious adverse effects, while underexposure may compromise graft survival. A pharmacokinetic model was developed to guide weight-banded dosing and account for factors such as blood counts, kidney function, developmental stage, and interactions with azole antifungals. The model provides practical, age-specific dosing ecommendations that address these interaction risks, supporting safer and more effective immunosuppression in this vulnerable group. Immunoglobulin is essential for children with antibody deficiencies, whether due to an underlying immune disorder or acquired after medical treatments. As a limited, blood-derived resource, it must be used safely and cost-effectively. This research introduced an innovative approach, measuring IgM levels, to estimate a child’s ability to produce their own antibodies thereby being able to build a model to describe the data. This can guide personalised dosing, ensuring those most in need receive adequate treatment while preserving supplies. Favipiravir, an experimental antiviral, was studied in immunocompromised children for the first time. Its pharmacokinetic was characterised, revealing age-related differences. The findings inform local dosing guidance and provide a framework for the pharmacokinetic evaluation of novel therapeutics in rare or urgent clinical contexts. Across these medicines, the thesis demonstrates how paediatric PK modelling can translate into practical dosing strategies, bridge evidence gaps for vulnerable populations, and lay the groundwork for national prescribing recommendations and future clinical decision-support tools.

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