Title: Personalising azole antifungals and immunoglobulin therapies for haematopoietic stem cell transplantation and antibody deficient children using pharmacokinetic population models.
Funder: Health Education England

Abstract: Background Personalised medicine can improve therapeutic management of individuals or a cohort. Patients with antibody deficiency(AD) and those undergoing haematopoietic stem cell transplantation(HSCT) require precise polypharmacy management to remain well. Antifungals, immunosuppression and immunoglobulin replacement are used to prevent life-threatening complications in these patients, but evidence to support precision dosing is lacking. Azole antifungals(azoles) pharmacokinetics/pharmacodynamics(PKPD) Itraconazole, posaconazole and voriconazole are used to prevent and treat invasive fungal diseases. Itraconazole and posaconazole lack paediatric licences, whereas voriconazole is licensed from >2 years of age. In 2018, we demonstrated that therapeutic posaconazole concentration was challenging to achieve in young children. Literature also describes difficulties in achieving therapeutic targets of other azoles. Drug-drug interactionCYP3A4 enzyme is responsible for adverse drug-drug interactions. CYP3A7 is expressed instead of CYP3A4 in infants up to 12 months of age. Most paediatric drug-drug interaction information is extrapolated from adult data. The differential expression and activity of these enzymes can significantly alter drug depositions in small children. This is particularly important in HSCT children who receive concurrent therapies(e.g. ciclosporin, azoles) metabolised by these enzymes. Immunoglobulin in AD patients The UK's immunoglobulin usage has been rationalised due to limited supply. The minimum immunoglobulin plasma level to prevent various infections in AD patients remains undefined. Optimising dosage and target level can help utilise immunoglobulin effectively. Research questions What is the optimal azoles dose for HSCT children? How do azoles affect ciclosporin concentration quantitatively? What is the optimal subcutaneous dose and lowest effective immunoglobulin plasma level to prevent infection in AD children?GOSH parents reviewed this proposal and confirmed its relevance to patient care, contributed to plain English summary and result dissemination method. AimsTo develop treatment algorithms for the optimum clinical dose regimens of studied medicines.Objectives To investigate the: PKPD and dose of azoles(all administration routes) age-stratified CYP3A-mediated drug interaction between ciclosporin and azoles quantitatively optimal subcutaneous immunoglobulin dose and blood level to reduce infection risk Method Population PKPD non-linear mixed-effects models will be built. Retrospective patient data will be analysed to optimise pharmacotherapy in HSCT and AD children aged 0 to 18 years. Delivery timelines I will dedicate the first two years to research question 1 and 2 whilst adopting PKPD modelling and research skills and completing my clinical development courses. I will then apply my refined modelling skills to the third question in my third(final) year. I will meet with my supervisory team and patient involvement panel throughout my fellowship to review progress and seek feedback on results and future direction. Anticipated impact and dissemination Collaboration with the local teams will ensure the research results(new dosing and therapeutic-monitoring guidelines) be incorporated into patients' daily care. This project will feed into the national paediatric Antifungal Stewardship programme and UK Primary Immunodeficiency Network aiming to guide national prescribing in paediatrics. After implementation at local level, the effects of proposed models in practice will be investigated via an audit. Summary findings co-authored with parents representatives will be disseminate to public. Results will be publicised as peer-reviewed publications and in conferences.

Lay abstract: TitlePersonalising antifungal and immunoglobulin therapies for children undergoing Bone Marrow Transplantation and children who cannot produce antibodies (Antibody deficiency) using computer models. Plain English Summary Studies are usually carried out in adults to check how safe and how well medicines work. They provide valuable information about how much to give and side-effects. Medicines work differently in children compared to adults in terms of their action and how they are cleared from the body. Due to various challenges, studies in children are not always available. As a result, adult data is used to suggest medicine amounts for children. Children, however, are not 'small adults.' Personalising doses based on information derived from children will help children obtain effective therapy. Antifungals in Bone Marrow Transplantation (BMT) BMT cures children with life-threatening conditions. However, the patient's body may reject these life-saving cells or, on the other hand, be attacked by them. Therefore, these patients are given medicines called immunosuppressants (ciclosporin) to stop them fighting each other and chemotherapies to stop disease-causing cells dividing. Because of these medicines, BMT patients are at high risk of infection. Antifungals (itraconazole, posaconazole and voriconazole) are given to prevent or treat fatal fungal infections. Immunoglobulin replacement therapy Therapeutic immunoglobulin products contain a wide mixture of antibodies that help fight infections. Patients whose bodies' defence (immune system) not able to make antibodies are given regular immunoglobulin through a vein (intravenous) or through the skin (subcutaneous) to prevent infections. However, the minimum immunoglobulin blood levels required to prevent various infections is unknown. With a limited immunoglobulin supply within the UK, finding the dose required to achieve the lowest effective blood level will help using immunoglobulin effectively. Challenges in using antifungals and immunoglobulin in children Blood tests are needed to check whether the dose is right for the child Effective levels may take several attempts to achieve and lead to ineffective treatment or harm The effect of antifungals on ciclosporin levels is unknown. High ciclosporin levels cause harmful side effects, and low levels may cause fatal transplant-related complications Guidance on adjusting ciclosporin doses when given with these antifungals is not available The minimum effective immunoglobulin level needed to prevent infection in patients with antibody deficiency is unknownThe aims of this project are to find: a safer, tailored and evidence-based paediatric dose for itraconazole, posaconazole, voriconazole guidance on ciclosporin dose adjustment when used with antifungals the right amount of subcutaneous immunoglobulin to achieve preferred immunoglobulin levels and the minimal level required to prevent infection/hospitalisationMethod This study will use the retrospective data collected from BMT and antibody deficient patients aged between 0 and 18 years since 2010. Using a computer tool, a model studying how the body handles a drug in a population (population pharmacokinetic model) will be built to address the aims of this study. Benefits Tailored antifungals, ciclosporin and immunoglobulin dose for children Improve patient safety and avoid side effects Avoid wastage and use NHS resources effectively Generate more data to support using medicines in childrenResults and dissemination Patient/parents representatives will be invited to contribute to the study plan and produce a booklet to share the results with the public. Results will also be communicated via conferences, scientific journals and national networks to guide prescribing in children. A prescribing tool will be developed to guide prescribers on managing the medicines studied.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE