Emma is a PhD student in cancer pharmacology at Newcastle University. She graduated with a BSc (Hons) in Biomedical Science from the University of Brighton before completing an MSc in Cancer Cell Biology and Therapeutics at Cardiff University. Emma began her PhD in 2023,
where her work focuses on pharmacokinetics and treatment optimisation for paediatric stem cell transplantation and cancer therapy with a particular interest in treatment‑related toxicity and evidence‑based dosing strategies.
Pharmacokinetics and Therapeutic Drug Monitoring
What happens to a drug when it enters the body?
How does this affect how well the drug works, or why it sometimes causes unwanted effects?
And can understanding this help us make treatments better?
Pharmacokinetics (PK) is the study of what the body does to a drug. PK looks at the journey a drug takes after administration: how it is absorbed (absorption), where it goes (distribution), how we break it down (metabolism) and how we subsequently get rid of it (excretion).
Our research focuses on characterising and understanding the variability in these properties and learning how we can utilise this to improve treatment for patients, particularly in children.
When it comes to pharmacology, children are not just little adults. Developmental changes experienced throughout childhood (developing organs, changing physiology and unique disease profiles) can manifest in profound changes in drug responses. Traditional dosing principles often based on weight, size or age banding may not be reflective of this complexity and are often not based on clear pharmacological rationale.
Therapeutic drug monitoring (TDM) involves the measurement of drug concentrations in patient blood samples with the aim of optimising dosing in the individual by personalising dosing. This technique can allow for real time dose adjustments to maintain a more targeted, and hopefully more effective, drug exposure. This approach is especially valuable in paediatrics, where PK variability is greater, susceptibility to toxicity differs in developing organs, and robust dosing data are often lacking.
Personalised Dosing of Fludarabine in CAR T-Cell Therapy
Paediatric cancer treatment, particularly the chemotherapy given before CAR T-cell therapy for leukaemia, is an example of how these techniques are already benefiting patients in the UK.
B‑cell acute lymphoblastic leukaemia (B‑ALL) is the most common cancer affecting children and young adults, with around 400 new cases diagnosed each year in the UK[1]. While first-line therapy is often successful, 10-20% of patients relapse or fail to respond to therapy (refractory disease). For those patients with relapsed or refractory (r/r) disease, treatment options are limited, and outcomes are poor. Chimeric antigen receptor (CAR) T‑cell therapy, involving genetically engineering a patient’s own T cells to recognise leukemic cells, is an exciting and potentially curative emerging treatment option for these patients.
Up to 90% of children achieve complete remission after receiving CAR T-cell therapy. The challenge is sustaining that benefit over time, as within 1-2 years, around half of patients experience CAR T-cell failure, including disease relapse[2].
Lymphodepleting chemotherapy with fludarabine and cyclophosphamide is a crucial part of preparing patients for CAR T-cell infusion, helping to create the right environment for the new cells to expand and persist.
Previous studies have shown that the systemic exposure (AUC) of fludarabine plays a critical role in patient outcomes. Exposures outside the range of 14-20 mg·h/L are associated with lower survival and higher rates of treatment failure[3]. However, achieving this level consistently is difficult, as fludarabine exposure varies widely in paediatric patients. This is what my research focuses on, assessing if patient outcomes can be improved by individualising fludarabine dosing.
Commonly, children receive fludarabine over 4 days as part of their lymphodepleting chemotherapy. In our study, we take blood samples over the first 24 hours following the dose on day 1 and measure the fludarabine concentration in each sample. These measurements, along with a population PK model, allow us to calculate the patient’s exposure (cAUC) and determine if this sits within the optimal window. We use these results in real time to guide dosing for the remainder of the 4 days to target exposure to within that optimal window. We offer further sampling after a dose adjustment to re-measure concentrations, re-calculate the exposure and confirm the dose was appropriate.
What we’ve found so far is that 78% of patients achieve exposures outside of the range. Approximately 43% of patients achieved exposures below the range, potentially putting them at risk of disease relapse and treatment failure. The other 35% achieved exposures above the range, putting them at higher risk of drug-related toxicities. But the good news is, that for the patients who we dose adjusted and ran confirmatory further sampling, all dose adjustments were successful, bringing the patients to within 6% of the exposure targeted.
This is just the beginning of this work; we have shown that it is important to monitor fludarabine exposure in real time and that it is feasible for patients treated across the UK. We are now opening a dedicated clinical trial called “Goldilocks” funded by the little princess trust, that will allow us to perform real time monitoring of fludarabine in r/r B-ALL CAR T-cell patients across the UK (ISRCTN10473740). We will compare these patient outcomes with patients who have previously had the standard dosing of fludarabine.
Pharmacology 2025
I was fortunate enough to present my research at Pharmacology 2025 in Belfast in December. It was a great opportunity to share our work with a broad pharmacology audience. The conference programme was extensive, with loads of parallel sessions, and there were definitely points where I was torn about which session to go to. I ended up really enjoying the talks on pharmacology in pregnancy and innovations in drug discovery.
Presenting my poster was a great experience. At a conference with over 700 attendees, the poster section of the exhibition hall can seem overwhelming at first glance, but I ended up really enjoying the experience. I had lots of engaging conversations with people both at my poster but also while wandering around looking at all the other posters and learning about all corners of pharmacology. As an early career researcher, it was invaluable to have people take the time to chat through my data, show interest in my work and offer me thoughtful feedback.
Winning the best Clinical Pharmacology Poster Prize and the overall best Poster Prize was the icing on top of the cake for my BPS experience. I can’t wait to do it all again in Manchester this year!
References
- CCLG. (2022). Acute Lymphoblastic Leukaemia (ALL) in children, The Children’s & Young People's Cancer Association. https://www.cclg.org.uk/about-cancer/cancer-children-and-young-people/types-cancer-children-and-young-people/leukaemia-children/acute-lymphoblastic-leukaemia-all-children
- Maude SL, L. T., Buechner J, Rives S, Boyer M, Bittencourt H,. (2018). Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine, 378(5), 439-448. https://doi.org/10.1056/NEJMoa1709866
- Dekker, L., Calkoen, F. G., et al (2022). Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Blood Adv, 6(7), 1969-1976. https://doi.org/10.1182/bloodadvances.2021006700
